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Departamento de Bioquímica y Biología Molecular (C.L.-O.), Facultad de Medicina, Universidad de Oviedo 33006, Oviedo, Spain; and Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada, M5G 1X5 and Department of Laboratory Medicine and Pathobiology, University of Toronto (E.P.D.), Toronto, Ontario M5G 1L5, Canada
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 Top Abstract I. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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In males, the breasts are rarely affected by breast cancer. The androgenic dominance over estrogens in males keeps the breasts underdeveloped throughout life. However, even for male breast cancer, the major contributing role of steroid hormones is evident from clinical observations. For example, a number of conditions have been established, almost all related to hypoandrogenism, that increase the risk of breast cancer in males. These include Klinefelter’s syndrome, testicular atrophy, orchitis, undescended testes, testicular trauma, infertility, and defects in androgen receptor (AR) genes (6).
Prostate cancer is the most common malignancy among males in
North America. In the United States, about 200,000 new cases are
diagnosed every year and about 45,000 men die annually from the
disease. Overall, about one in every nine men will be diagnosed with
prostate cancer during their lifetime. These numbers are strikingly
similar to those already mentioned for breast cancer (7). Similarly to
breast cancer, the pathogenesis of the disease is also obscure. Major
risk factors include age, ethnicity, family history, and steroid
hormones. While the rate of increase of breast cancer incidence
declines postmenopausally in women (1), the rate of increase of
prostate cancer incidence increases continually with age. This
phenomenon is likely linked to the continuation of testicular function
in males throughout life and the cessation of ovarian function during
the female menopause. The involvement of steroid hormones in the
pathogenesis and progression of prostate cancer has been suggested for
many years. Huggins, as early as 1940, was able to achieve transient
remission of prostate cancer with orchiectomy and with administration
of estrogens (8, 9). Currently, pharmacological androgen ablation
therapy is achieved either by blocking androgen production or activity
by administration of antiandrogens or other agents. Males who have
diminished androgen production due to castration, hypogonadism, or
enzyme defects of androgen metabolism (e.g., 5-reductase)
have minimal risk for prostate cancer.
We and others have hypothesized that breast and prostate cancer may represent, in some aspects, homologous cancers in females and males, respectively. Breast and prostate cancer are now the two most common cancers with a roughly equal lifetime risk. They are both influenced strongly by steroid hormones, gonadal removal reduces the risk dramatically in both sexes, and antiestrogens are beneficial and possibly preventive for breast cancer while antiandrogens are beneficial and possibly preventive for prostate cancer (10). Additionally, these two cancers have parallel incidence rates in various countries, and there is evidence suggesting that they are both influenced by the same dietary factors (e.g., fat consumption). Macklin, as early as 1954, provided evidence for a significantly higher frequency of prostate cancer among relatives of breast cancer patients and proposed for the first time that prostate cancer may be the male equivalent of some female breast cancers (11). In the last few years, additional epidemiological, genetic, and biochemical findings support the view that these two cancers have many similar features. Here, we review the current knowledge, focusing on common features, in an attempt to understand these malignancies better and possibly trigger some new thinking into their pathogenesis and progression. The reader, however, should be aware that there may be a bias in our presentation since we have selected literature that cites a connection between the two cancers. Other literature that either does not cite a connection or cites a connection of breast or prostate cancer with other cancers was not systematically reviewed since it falls outside the scope of our manuscript. This biased presentation may be specially relevant in the discussion of the putative genetic and biochemical abnormalities shared by breast and prostate cancer, since many of the associations described in the literature are not exclusive of these tumors and could merely reflect the general process of carcinogenesis. Thus, in the case of genetic abnormalities, it is well known that breast and prostate cancer, as well as other human carcinomas, result from the accumulation of genetic lesions in a variety of oncogenes and tumor suppressor genes. However, none of these genes is exclusively damaged in breast and/or prostate carcinomas, thus limiting their value in the context of this review. Consequently, we have focused the discussion on those few genes like AR or breast cancer susceptibility genes BRCA1 and BRCA2, which have a high degree of specificity for one of the two tumors (prostate or breast cancer, respectively), but whose involvement in the other tumor (breast or prostate cancer) has been suggested through epidemiological, biochemical, or mutational analysis. Nevertheless, it must be emphasized that the contribution of common genetic factors to the overall incidence of both tumor types may be low in quantitative terms and circumscribed to a specific subgroup of patients. A similar consideration must be done in the discussion of putative common biochemical features shared by breast and prostate carcinomas. In this case, the finding of commonalities in the expression pattern of diverse bio-markers associated with the development and progression of breast and prostate cancer may be only a consequence of general alterations of critical cell functions occurring during the malignant transformation of human cells, but not specifically of mammary or prostatic epithelial cells. Therefore, we have focused the discussion on those biochemical markers that may be of special interest for the biology of these two carcinomas because of their relative specificity of expression in breast or prostate carcinomas when compared with tumors from other sources, or by the occurrence of shared mechanisms of hormonal control mediating their up- or down-regulation in these two hormone-sensitive cancers. Likewise, the discussion of commonalities in the expression and regulation of growth factors associated with breast and prostate cancer may be of limited value because many growth factor pathways are universally altered in most human malignancies. Consequently, and as in the case of biochemical markers discussed above, we have focused our attention on those growth factors that may be of special relevance in the context of breast and prostate cancer by both the relative specificity of the alterations and the finding of common hormonal networks underlying their effects on these carcinomas. Taken together, we must conclude from these observations that, based on data of the few comparative analyses currently available, the existence of common factors in breast and prostate cancer is still speculative in many aspects. The next sections present a summary of available epidemiological, genetic, and biochemical data supporting associations between both tumors, with a special emphasis on describing the common hormonal aspects underlying the observed associations.
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II. Epidemiological Evidence Associating Breast and Prostate Cancer |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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Thiessen (12), in 1974, after analysis of the familial incidence and distribution of all malignancies in a group of 145 breast cancer patients, compared with that of 139 randomized control patients, reported that significantly higher incidences of only uterine, prostatic, and breast cancer were found among both maternal and paternal relatives of the breast cancer patients. On this basis, he proposed that the mammary gland is part of an integrated genital organ system whose different parts share unique biological and pathological characteristics, including hormone responsiveness and cancer susceptibility. He also hypothesized the existence of some common etiological factor that could operate in the development of tumors in diverse reproductive organs, including breast and prostate. In 1982, Cannon et al. (13), in a study of genetic epidemiology of prostate cancer in a population from the Utah Mormon genealogy, showed a significant coaggregation of prostate cancer with breast cancer. More recently, in case-control studies based on anamnestic data, Andrieu et al. (14) and Rosenblatt et al. (15) did not find evidence of association between these two tumors. By contrast, Tulinius et al. (16) in a large cohort study including 1539 Icelandic women with breast cancer, reported that the risk of prostate cancer was significantly raised for all male relatives, as well as for first-degree relatives, and second-degree relatives of breast cancer patients. It is noteworthy that in this study the information concerning which family members had cancer was obtained from the Icelandic Cancer Registry, whereas genealogical trees were constructed by using information from records of the genetics committee of the University of Iceland, thus avoiding possible bias generated by directly asking the family members about the structure and cancer cases in their families. Similarly, Anderson and Badzioch (17) found that a family history of prostate cancer in male breast cancer patients resulted in a 4-fold increased breast cancer risk in first-degree female relatives compared with that in male breast cancer families with no history of prostate cancer. By contrast, a family history of lung cancer, colon cancer, or melanoma had no effect on increasing risk of breast cancer. Finally, a series of recent studies concerning the putative familial clustering of breast and prostate cancer have provided opposite results. Thus, Isaacs et al. (18) in a study of families selected because of the presence of prostate cancer did not find increased risks for cancer at other sites, such as breast, ovary, or endometrium. Similarly, Negri et al. (19) did not observe an elevated risk of prostate cancer in relatives of breast cancer patients. By contrast, Sellers et al. (20), in a large prospective cohort study of Iowa women, noted that a family history of breast and prostate cancers is a stronger risk factor for postmenopausal breast cancer than is a family history of breast cancer alone. The reasons for the discrepancies between the different epidemiological studies are unclear, although Anderson and Badzioch (21) have pointed out a number of potential explanations, including differences in the study populations, variability in the size of families, or some peculiarity of sampling. It is also possible that methodological aspects could influence the final results, since coaggregations between breast and prostate cancers were specially noted in those studies involving very large pedigrees in which only those relatives with medically documented tumors were considered eligible for the study.
Therefore, it seems clear that not all data on the potential association between breast cancer in females and prostate cancer in males are univocal. However, a number of studies performed by different groups in populations of different geographic origin appear to indicate that a family history of breast cancer may have a significant influence on prostate cancer risk and vice versa. This observed association between breast cancer and prostate cancer suggests that, at least in some cases, both tumors may share common factors, either genetic or epigenetic, that could finally lead to the development and progression of these malignancies. Among the different factors that can be shared by breast and prostate cancers, three of them deserve special attention. First, and considering that both carcinomas arise in hormonally regulated tissues, it is conceivable that common hormone alterations could play a role in the development or progression of both tumors. On the other hand, and since the above mentioned studies suggested a familial coaggregation of breast and prostate cancer in different populations from different origins, it seems clear that in addition to being hormonally related, these tumors may also share some genetic abnormalities that could contribute to the acquisition of the malignant phenotype by both mammary and prostatic epithelial cells. Finally, it is also possible that the coaggregation of these highly prevalent tumors may be also influenced by a number of lifestyle and environmental factors, including dietary factors, whose importance in the development of human cancer is becoming increasingly apparent.
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III. Incidence of Breast and Prostate Cancer in Different Countries: Dietary Factors |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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The highest correlation between cancer incidences was observed between
breast and prostate and breast and endometrial cancers (Fig. 1 and data not shown). The lowest
incidence rates of both breast and prostate cancers were found in Japan
and Hong Kong and the highest incidence rates were found in the USA and
Canada. Similar data were obtained for endometrial cancer (not shown).
These indirect findings, taken together with migrand studies, which
suggest that cancer incidence rates change within two to three
generations when low risk populations migrate to countries with high
risk, suggest that common environmental factors may be responsible for
these cancers.
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Among all dietary factors, fat consumption has received the greatest
attention (36). The connection between high-fat diet and increased
cancer risk is supported by animal studies (37). In humans, breast
cancer risk (22, 36) and prostate cancer risk (22, 38, 39) were found
to increase with increased fat consumption. Although such associations
are consistent between many studies, others question the validity of
the data because of the presence of many confounders and the poor
accuracy of obtaining food intake data (40, 41). It is expected that
the role of dietary fat in the development of breast cancer will be
further elucidated when a primary prevention trial among women age
50-79 is complete (1, 10). The Women’s Health Initiative is a
randomized, placebo-controlled trial with three different
interventions, one of which is dietary, aiming to reduce fat intake to
20% of total calories (from about 40% currently) and to increase
intake of fruits and vegetables. In the same trial, another
intervention includes vitamin D and calcium supplements (1). Other
chemoprevention trials are underway in many countries (10). Prentice
and Sheppard calculated, based on fat disappearance data, that a 50%
reduction in fat consumption may reduce the relative risk of women of
age 55-69 yr for breast cancer from 1.00 to 0.39 and in men for
prostate cancer from 1.00 to 0.17. Such benefits, they postulate, may
also be seen for endometrial, colon, rectal, and ovarian cancer (22).
The biological basis of fat consumption and risk for breast and
prostate cancer is not known, but there is evidence that fat intake
alters steroid hormone concentration in serum. For example, it has been
reported that plasma estradiol levels are reduced in postmenopausal
women on low-fat diets (42). Also, there is evidence that a low-fat
diet may reduce testosterone levels in adulthood (43) or may modify
5-reductase activity (39).
The association between breast cancer and fat consumption has recently been reviewed, and it was concluded that, in the absence of data from dietary intervention trials, the weight of available evidence suggests that the type and amount of fat in the diet is related to postmenopausal breast cancer (44). The associations between diet and breast and prostate cancer are also evident from migrant studies. Migrant groups usually adopt dietary patterns similar to those of their new country within a few years after migration. Statistical analysis has shown that dietary fat alone can provide an explanation for the major changes in cancer risk that followed Japanese migration to the United States. For example, Tominaga (45) reported relative risks (RR) of 3.5 and 5.7 for breast and prostate cancer, respectively, in Japanese migrants to the United States. The calculated higher risks, based on changes in fat consumption alone, are 2.9 and 7.2, respectively, in close agreement with the observed risks.
The current epidemiological data suggest that the epidemic of breast and prostate cancer may be partially attributable to increased fat consumption, increased caloric intake during growth, low fiber, vegetable, and fruit consumption, and other lifestyle factors including exercise, alcohol, and smoking (22, 41, 43). Refinements in our knowledge regarding fat consumption and its connection to cancer suggest that specific fatty acids (e.g., the n-6 polyunsaturated fatty acids) may be more potent tumor enhancers than other unsaturated or saturated fatty acids (46-49). Hopefully, the studies that are now underway will provide us with more insights that will be useful in designing successful prevention strategies.
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IV. Genetic Abnormalities Common to Breast and Prostate Cancer |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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A. AR alterations in prostate cancer
The AR is a transcription factor that plays an essential role in a
wide number of biological functions, from development and maintenance
of male reproductive functions to modulation of immune responses or
development of neural tissues (75). Like other nuclear receptors, AR
exerts its biological effects after binding of circulating androgens
mainly transported to target tissues by carrier proteins (76). Androgen
binding induces a conformational change in the AR that facilitates
receptor homodimerization, nuclear transport, and interaction with DNA.
The binding of the AR to the hormone response elements (HRE) present in
target genes results in the regulation of their transcriptional
activity (77). The structure of the AR is also similar to that of the
other members of the steroid-receptor family of ligand-dependent
transcription factors, with an N-terminal transactivating domain (exon
A), a central DNA-binding domain (exons B and C), and a C-terminal
hormone-binding domain (exons D through H) (78).
Because of the essential participation of AR in the regulation of
prostate growth and in the maintenance of prostatic function, over the
last years many groups have tried to define the potential role of this
hormone receptor in the development and progression of prostate cancer.
The first studies in this regard were based on analysis of the AR
functionality in prostate carcinomas by using ligand-binding activity
assays and immunohistochemical techniques (79, 80). However, results of
a series of structure-function relationship studies of mutated ARs have
revealed that ligand binding or immunoreactivity are not the most
appropriate indicators of AR functionality. Thus, investigators have
described the occurrence of mutant ARs that do not bind androgens but
are constitutively active, or receptors that bind steroids with high
affinity but are nonfunctional as transcription factors (81, 82). As a
consequence of these observations, more recent studies have examined
the possibility that alterations in the integrity of the AR gene in
prostate carcinomas could be a more accurate index of the AR
functionality in these tumors (83) (Fig. 2). The first
indication that structural changes in the AR could be important in the
progression of prostate cancer was provided by the detection in LNCaP
prostate cancer cells of a point mutation in the ligand-binding domain
of this receptor (84). Interestingly, this mutation (Thr877Ala) leads
to a decrease in steroid-binding specificity and completely reverses
the effect of commonly used antiandrogens (84). After these findings in
established cancer cell lines, several groups have attempted to
demonstrate the putative occurrence of AR gene mutations also in tumor
tissue specimens. The first description of an AR abnormality in human
prostate cancer was done by Newmark et al. in 1992 (85).
These authors found a point mutation (Val730 Met) in 1 of 26
early-stage prostatic carcinomas. Thereafter, other groups have
reported that AR mutations may also occur in a small percentage of
advanced cancers (86-92). By contrast, Ruizeveld de Winter et
al. (93) did not detect mutations in AR genes from 18 patients
with hormone-resistant, locally progressive prostate cancer. Although
these studies appear to indicate that the frequency of AR mutations is
low, even in advanced prostate cancer, recent work using improved
strategies for mutational analysis of AR have found a higher proportion
of genetic abnormalities in either latent prostatic carcinomas or in
metastatic disease. Thus, Takahashi et al. (94) have found
that a significant proportion of latent prostate carcinomas from
Japanese men contain genetic alterations in the AR gene (18 of 79),
while no such mutations were found in 43 latent carcinomas from
American men. On the other hand, Gaddipati et al. (95) have
shown the presence of the above described mutant Thr877Ala, in 6 of 24
prostatic tissue specimens obtained from patients with metastatic
prostate cancer, providing the first evidence that a mutational hotspot
may occur in the AR gene in a subset of these tumors. More recently,
Taplin et al. (96) have shown the presence of AR gene
mutations in metastatic cells from 5 of 10 patients with
androgen-independent prostate cancer, which has led them to conclude
that mutations in this gene are not as rare as previously considered by
other authors. Consistent with this, Tilley et al. (97) have
found somatic mutations in 44% of primary prostate tumors taken before
initiation of androgen ablation therapy. The presence of AR amino acid
substitutions was found not only in the hormone-binding domain, which
is the region examined in most studies mentioned above, but also in the
remaining functional domains of this protein. In fact, about 50% of
the mutations found by Tilley et al. in prostatic tumors
were within exon A of the AR, which encompasses 58% of the coding
region of the gene, but whose integrity has not been examined in
virtually any mutational study of the AR gene. These results
demonstrate the need to examine the complete AR-coding region before
any conclusion on the structural integrity of the AR gene in prostate
carcinomas can be reached. It is also remarkable that Tilley et
al. (97) have provided evidence that mutations found in AR are not
a consequence of the generalized genetic instability inherent to
different malignant processes, suggesting that they have functional
relevance and do not simply reflect the neoplastic state. In fact,
these authors have observed that the occurrence of the AR mutations in
the studied prostatic carcinomas was associated with a rapid failure of
subsequent hormonal therapies. Therefore, it seems that AR gene
mutations may occur commonly in advanced prostate cancers before
endocrine treatment, thereby contributing to the observed altered
androgen responsiveness of these tumors, and finally leading to their
progression to androgen independence. Finally, two germline point
mutations in the 5'-untranslated region of the AR gene have been
recently described in men with prostate cancer. It has been
proposed that these mutations may contribute to the disease by altering
rates of transcription and/or translation of this gene (98).
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In conclusion, it appears that AR gene alterations in prostate carcinomas and in metastatic tissue derived from these tumors are much more frequent than originally suggested. These genetic defects include point mutations, gene amplification, or variations in the length of trinucleotide repeats. At present, there is a lack of compelling evidence associating receptor variants with response to endocrine therapy, or clinical course of the disease. However, functional analysis of AR variants appear to indicate that they confer upon this receptor a broadening of ligand specificity, making it capable of activation by estrogens, progesterone, antiandrogens, and adrenal androgens in addition to testicular androgens (57, 84, 86, 90-92, 96, 97, 110). This is in marked contrast with the findings in other diseases involving abnormalities in the AR gene, such as androgen insensitivity syndromes or diseases generated by trinucleotide expansion in the CAG region of the AR, which are usually accompanied by loss of AR function (76). As a consequence of these gain-of-function mutations detected in prostatic carcinomas, tumor cells may proliferate in an androgen-deficient environment or during antiandrogen therapy. Therefore, these findings may explain why these carcinomas become refractory to endocrine therapy and could lead to the development of more effective hormonal therapeutic strategies as well as predictive tests for therapy failure.
B. AR alterations in breast cancer
Since, according to the above mentioned data, there was a
significant body of epidemiological evidence suggesting an association
between breast and prostatic cancer, it seemed likely that if AR gene
alterations are important in the development of prostate cancer,
similar abnormalities could also occur in some cases of breast cancer.
The first indication that AR may also be altered in breast carcinomas
was provided by Wooster et al. (58) who reported an AR
germline mutation in two brothers with breast cancer and Reifenstein
syndrome, a partial androgen insensitivity syndrome originally
described as an X-linked familial syndrome of hypospadias, infertility,
and gynecomastia in association with normal 17-ketosteroid excretion
and high FSH levels (76). The mutation results in the substitution
Arg607Gln, within the region encoding the DNA-binding domain of the
receptor. More recently, Lobaccaro et al. (59, 60)
identified another germline mutation in the AR gene, in a man with
lobular carcinoma of the breast and partial androgen insensitivity
syndrome. This mutation leads to an Arg608Lys substitution, also in the
DNA-binding domain of the receptor and is identical to an alteration
previously described in a patient with partial androgen insensitivity
syndrome (111). Two main hypotheses have been proposed to explain
breast cancer development linked to AR mutations (58-60). The first one
involves the loss of a putative protective effect of androgens, which
could explain the low incidence of breast carcinomas in males. However,
in light of the above observations in prostate carcinomas, it is also
possible that the development of breast carcinomas associated with AR
mutations could be a consequence of the acquisition of additional
properties by the mutated AR proteins. Thus, they could have an altered
pattern of hormone responsiveness, including the acquisition of the
ability to bind ligands other than testicular androgens, thereby
extending their transactivating properties. In any case, elucidation of
the potential role of AR in the development of some breast carcinomas
will require the identification of additional cases and functional
studies with the identified mutant receptors. Finally, it would also be
of interest to look for the presence of somatic AR gene alterations in
sporadic cases of breast carcinomas in both males and females. In this
regard, Hiort et al. (112) have recently reported the
absence of mutations in exons 2-8 of the AR gene in breast carcinomas
from 11 males without clinical evidence of androgen insensitivity,
suggesting that AR gene mutations do not play a major role in the
development of sporadic male breast cancer. By contrast, one should
note the recent identification of an exon 3-deleted splicing variant AR
in breast cancer cell lines and tissues (62). This AR variant is
expressed at high levels in some breast carcinomas (7 of 31), whereas
in normal breast tissues its expression is undetectable. Also, recent
immunohistochemical analysis in breast tumor specimens has suggested
that structurally altered forms of the receptor, including
amino-terminal truncated variants, may be present in a significant
proportion of breast carcinomas (61).
In summary, a series of recent studies performed by different groups has revealed that inherited and acquired AR alterations may occur in breast carcinomas (58-62). The number of described AR abnormalities in breast cancer is low, suggesting that these would only affect a small subgroup of patients. However, it is also remarkable that this field has been largely unexplored and few studies have specifically addressed the role of AR mutations in breast cancer. Nevertheless, these preliminary mutational data, together with the finding of abnormalities in androgen levels in patients with breast cancer (113-115) and the widespread expression of AR in primary breast carcinomas (61, 116, 117), suggest that AR-mediated pathways may be of biological and clinical relevance in breast cancer. Further studies and functional characterization of AR variants in breast carcinomas, in a similar fashion to studies performed in prostatic carcinomas, will be required to clarify the putative contribution of AR to breast cancer cell growth and response or resistance to hormonal therapies.
C. BRCA1 and BRCA2 alterations in breast cancer
Evidence for a genetic component in breast cancer risk was first
noted by Paul Broca more than one century ago, when he described four
generations of breast cancer in his wife’s family (118). Since then,
extensive epidemiological analyses of breast cancer cases that appear
to be clustered in families have been reported. The results of these
analyses suggest that about 5% of breast carcinomas may be explained
by inherited mutations in one or more genes. Despite the genetic
heterogeneity of breast cancer and the high prevalence of sporadic
disease, several breast cancer susceptibility loci have been identified
(119). The first of these genes, named BRCA1, was mapped in
1990 to chromosome 17q21 by genetic linkage analysis of large families
that included many cases of early-onset breast carcinomas (120) and has
been recently identified by Miki et al. (121) using
positional cloning methods. BRCA1 is composed of 22 coding
exons distributed over more than 100 kb of genomic DNA and encodes a
1863-amino acid protein, with two RING finger domains at its N-terminal
part, which are thought to be involved in DNA-binding or in
protein-protein interactions. In addition, BRCA1 shares a
conserved region with 53bp1 (a p53-binding protein) and rad9 (a yeast
protein involved in the control of the DNA damage-induced cell cycle
arrest), which has suggested that BRCA1 is likely to function in the
cell nucleus and may be involved in one or more cell cycle checkpoints
(122). In marked contrast with this proposal, it has also been
suggested that BRCA1 may play a role as a secreted protein, exhibiting
properties of a granin (123). To date, the function of BRCA1remains unclear, although a recent study has shown that this
protein inhibits the growth of breast epithelial cells (124). In
addition, studies on the developmental pattern of BRCA1
expression in mice suggest that it is involved in the process of
proliferation and differentiation in multiple tissues, notably in the
mammary gland in response to ovarian hormones (125). Furthermore,
analysis of BRCA1-/- mutant mice has suggested
that this protein may be a positive regulator of the cellular
proliferative processes that occur in early embryonic development
(126). On the other hand, Chapman and Verma (127) have recently
reported that the carboxy-terminal fragment of BRCA1 acts as
a strong transcriptional activator when fused to the GAL4 DNA-binding
domain. In addition, this activity is completely abolished in sequences
corresponding to four different mutations found in
BRCA1-linked families, thus providing direct evidence for
the possible function of BRCA1 as a transcription factor. Finally, a
new insight into BRCA1 function has has been provided by the
observation that it associates with the DNA-repair protein Rad51,
suggesting that BRCA1 may be a component of the double-strand-break DNA
repair pathway (128-130).
Mutations in the BRCA1 gene are thought to account for about half of the families susceptible to early-onset breast cancer and for at least 80% of families with clustered breast and ovarian cancers (131, 132). To date, germline BRCA1 mutations have been reported in more than 200 families from different geographic origins (131, 132). Germline BRCA1 mutations have also been found in young women with breast cancer who do not belong to families with multiple affected members (133). All classes of mutations are represented in these reported cases, including missense mutations, nonsense mutations, deletions, insertions, or intronic mutations, although the majority result in the production of a truncated protein. The finding of this large percentage of loss-of-function mutations is consistent with the hypothesis that BRCA1 acts as a tumor suppressor gene. It is also remarkable that most of the reported BRCA1 gene mutations have been identified in a single family, but a small number have been detected repeatedly. Of particular interest is a frameshift mutation caused by deletion of an AG dinucleotide (185delAG), which has been identified in more than 20 families of Ashkenazi Jewish descents and is estimated to occur at a frequency of about 1% in this population (134, 135).
The observation that less than half the families with multiple cases of breast cancer showed linkage to BRCA1 led to the proposal that there was at least an additional gene associated with breast cancer susceptibility. This result prompted another genomic linkage search and a second breast cancer susceptibility gene, named BRCA2, was located on chromosome 13q12 (136) and subsequently cloned (69, 137). BRCA2 is composed of 27 exons and encodes a protein of 3418-amino acid residues, which does not appear to be significantly similar to other proteins. Recent studies have shown that BRCA2 expression is coordinately regulated with BRCA1 expression during proliferation and differentiation in mammary epithelial cells, suggesting that both genes may act in the same pathway (138). Similarly to BRCA1, BRCA2 interacts with Rad51, providing additional support to the proposal that these proteins may be essential cofactors in the Rad51-mediated DNA repair of double-strand breaks (139). In fact, Connor et al. (140) have found evidence of a DNA repair defect in mice with a truncating BRCA2 mutation. Clinical studies have revealed that BRCA2 probably accounts for a proportion of early-onset breast cancer roughly equal to that resulting from BRCA1, and it may be of special importance in families with a high incidence of male breast cancer, but not in those with multiple cases of ovarian cancer. Mutational analysis of the BRCA2 gene in different populations has revealed that as in BRCA1, the identified mutations are widely distributed throughout the coding sequence of the gene, although evidence of some recurrent mutations has also been found (71, 141-144). Also of interest is the finding that BRCA2 mutations in families with the highest risk of ovarian cancer relative to breast cancer are clustered in a single exon of this gene (145). Finally, and also in common with BRCA1, diverse studies have shown that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian cancers (144-148).
D. BRCA1 and BRCA2 alterations in prostate cancer
As mentioned above, genetic epidemiological studies have provided
evidence for clustering of prostate and breast cancer in some families.
In addition, there is preliminary evidence that some plausible prostate
cancer genes, like AR, may be altered in some breast tumors. Therefore,
it seemed of interest to evaluate the possibility that genetic
abnormalities in breast cancer susceptibility genes, such as
BRCA1 and BRCA2, may also be associated with an
increased risk of prostate cancer in men. The first of these studies
was performed by Arason et al. (63) in seven large Icelandic
breast cancer families, two of which showed evidence of linkage to
BRCA1. These authors found that among presumed paternal
carriers of mutant breast cancer gene alleles, 7 of 16 (44%) had
developed prostate cancer, which led them to conclude that breast
cancer genes may predispose to prostate cancer in male carriers (63).
Additional evidence regarding the potential associations between
BRCA1 and prostate cancer risk comes from an analysis of 33
BRCA1-linked families performed by Ford et al.
(64). This analysis attempted to explore whether BRCA1 gene
carriers are at increased risk of cancer at sites other than breast or
ovary. According to the obtained results, there were statistically
significant excesses of prostate cancer and colon cancer in
BRCA1 carriers but not of cancer at any other sites. The
maximum likelihood estimate of the relative risk of prostate cancer in
BRCA1 carriers compared with the general population was
3.33. More recently, Gao et al. (65) in a study designed to
establish the possible involvement in prostate cancer of
BRCA1 and other potential tumor suppressor genes on
chromosome 17q, have reported a high frequency of loss of
heterozygosity at loci D17S856 and D17S855 (intragenic to
BRCA1) in prostate cancer. These results suggest that
BRCA1 and possibly other genes located within this region
(149) may be important in this cancer.
Although these studies seemed to confirm the hypothesis that some connection could exist between breast cancer susceptibility genes and prostate cancer, very recent work performed by Langston et al. (66) has provided more definitive evidence. These authors, in a study aimed at directly examining the potential role of BRCA1 mutations in the etiology of prostate cancer, have screened for germ-line BRCA1 mutations in a subset of men with prostate cancer. The subgroup of cases selected included men in whom genetic factors were most likely to be relevant, including early-onset and family history of both breast cancer and prostate cancer. Interestingly, a total of seven germ-line alterations in a series of 49 cases were found. One of them corresponded to the above mentioned frameshift mutation (185delAG), which is the most common germ-line BRCA1 mutation reported to date (134, 135). In addition, five structural abnormalities were identified in six patients but not in the 145 population-based controls. One of them is a 12-bp insertion in intron 20, which was identified in two different cases, and which had previously been found in a woman diagnosed with cervical cancer and breast cancer (133) and also in a woman with a history of breast and ovarian cancer (150). Although the functional consequences of this genetic alteration are unknown, it seems likely that this 12-bp insertion may affect RNA processing. The remaining four sequence variants have not been reported previously and are located in both coding and noncoding sequences. The fact that none of the sequence variants was identified in DNA from the control population suggests that they may represent alleles predisposing to disease. Finally, Struewing et al. (151) have also detected a BRCA1 frameshift mutant (5256delG) in a male patient affected with both breast and prostate cancer.
In addition to these genetic alterations in the first breast cancer susceptibility gene, studies of families linked to BRCA2 have revealed that prostate cancer risk is significantly increased in these families (67-74). Further analysis of some of these families has shown that in three of four BRCA2-linked Icelandic families, all prostate cancers tested are carriers of a 5-bp deletion in exon 9 (999del5), which is a recurrent mutation in Icelandic patients (71). Interestingly, prostate cancer patients carrying this mutation have significantly worse survival, which suggests that the BRCA2 mutation may be a possible marker for an aggressive disease in prostate cancer patients (73). Taken together, these data appear to indicate that mutations in the BRCA2 gene may also confer some risk of developing other malignancies, including prostate cancer, although detailed BRCA2 mutational studies in prostate carcinomas need to be done before more definitive conclusions can be reached.
Although it is clear that the basis for the hypothesis of common genetic features between some breast and prostate cancers is still speculative, two recently published studies have provided new and interesting insights. Struewing et al. (67), in an extensive study of the risk of cancer in a large group of Ashkenazi Jews, found a significantly elevated estimated risk of prostate cancer among carriers of BRCA1 or BRCA2 mutations. According to these data, the authors suggest that prostate cancer is part of the phenotype for these carriers. Similarly, Khan et al. (68), after analysis of germline BRCA1 and BRCA2 mutations in prostate carcinomas from a different population of Ashkenazi Jews, have concluded that mutations in these breast cancer susceptibility genes may increase the risk of prostate cancer.
In summary, there are some data indicating that alterations in the structural integrity of breast cancer susceptibility genes may indeed occur in prostate carcinomas. Nevertheless, according to available information, it appears that the contribution of germline BRCA1 or BRCA2 mutations to the overall incidence of prostate cancer is very small. In addition, the genetic association between breast and prostate cancer, due to BRCA1 and BRCA2, seems somewhat diluted by the fact that mutations in these genes also play a role in other tumors, including ovarian (150-153) and pancreatic carcinomas (154). Further studies and identification of additional prostate cancer patients with genetic alterations of BRCA1 and BRCA2 will be necessary to clarify the putative involvement of these genes in at least some cases of prostate cancer.
E. Other genes associated with breast or prostate cancer
In addition to the above described alterations in AR and
BRCA genes, acquired or inherited abnormalities in other
genes may occur in breast and prostate cancer. Analysis of reported
alterations in oncogenes and tumor suppressor genes in both breast and
prostate carcinomas reveals that somatic abnormalities are
heterogeneous in terms of involved genes and mechanisms operating for
their generation (reviewed in Ref. 50 -53). The class of genes that is
altered during the progression of normal mammary or prostatic cells to
hormone-independent or to highly aggressive metastatic cancer cells
includes classic tumor suppressor genes (p53,RB1)
and oncogenes (ras, myc, neu) (50-53, 155-159), as well as
genes involved in other processes such as cell-cycle inhibition,
cell-cell adhesion, angiogenesis, DNA repair, and apoptosis (160-167).
The mechanisms underlying these alterations are also diverse and
include point mutations, allelic deletions, high-level amplifications,
or de novo DNA methylation (50-53, 155-160, 168-173). This
heterogeneity is consistent with the idea, as originally proposed for
colorectal cancer (174), that breast and prostate carcinomas result
from the accumulation of genetic changes affecting a variety of genes
associated with critical cell functions. However, it must be emphasized
again that most of these genetic abnormalities are not exclusive to
these tumors and have lesser value in the context of this review, which
attempts to bring together factors common preferentially to breast and
prostate cancer. Nevertheless, it is clear that new oncogenes and tumor
suppressor genes important in the pathogenesis of these tumors are yet
to be identified. In this regard, it is noteworthy that very recent
studies from different groups have led to the identification in breast
or prostate carcinomas of a series of candidate oncogenes, tumor
suppressor, or metastasis suppressor genes, including H-cadherin (175),
maspin (176), MDC (177), PCTA1 (178),
PTI1 (179), MXI1 (180), PAC1 (181),
KAI1 (182), and thymosin ß15 (183), whose relevance to the
respective tumor processes has not as yet been definitively
established. In this context, it will be interesting to explore the
possibility that alterations in some of the new candidate genes
associated with breast cancer may be also found to occur in prostate
carcinomas and vice versa, thus helping to extend the
genetic associations between these two hormone-sensitive tumors. It is
also remarkable that the vast majority of genetic changes reported in
both breast and prostate carcinomas arise in somatic cells but
inherited defects may also predispose to both cancers. Interestingly,
studies of familial aggregation in both diseases have revealed that the
same percentage of breast or prostate cancers (
5%) may be directly
attributable to inherited cancer susceptibility alleles (50-53).
Familial breast and prostate cancer genes have now been mapped and, in
the case of breast cancer-susceptibility genes, some associations with
prostate cancer have been reported (63-74). Therefore, it will also be
of future interest to evaluate the possibility that alterations in the
familial prostate cancer gene (HPC1), recently mapped to the
long arm of chromosome 1 (184), may also occur in a subset of breast
carcinomas. Of interest is the preliminary report of a modest increase
in the occurrence of breast cancer in HPC1 families (185).
Further studies directed to examine the putative genetic commonalities
between breast and prostate cancers could provide better insights into
the mechanisms of progression of these hormonally dependent tumors and
generate novel ideas to improve therapeutic strategies.
|
V. Common Biochemical Features of Breast and Prostate Cancer |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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2-glycoprotein
(Zn-2-gp), and GCDFP-15, show a striking parallel
expression in both breast and prostate cancers. Importantly, such
expression is either very low or absent in other tumors. Thus, all of
them are up-regulated or down-regulated in a significant percentage of
tumors of both sites and in most cases, their production appears to be
dependent of common regulatory hormonal mechanisms. This section
summarizes the current evidence in the literature supporting our
proposal that these five proteins may represent examples of biochemical
similarities between breast and prostate cancer.
A. PSA
PSA was initially discovered in seminal plasma in the 1970s (186, 187). Purification was first achieved by Sensabaugh (188). PSA was
found to be a prostatic protein in 1977 (189) and was identified in
serum shortly afterward. Of paramount clinical importance were the
findings that serum PSA is increased in patients with prostate cancer
in comparison to normals and that changes of serum PSA concentration
are associated with cancer metastasis, recurrence, response to
treatment, and survival (190, 191). Currently, PSA is considered to be
the most valuable tumor marker due to its tissue specificity and it is
used widely for prostate cancer screening, diagnosis, and management.
Several reviews examine these issues in detail (192-196).
PSA is a 30-kDa serine protease that shares significant protein and
gene sequence homology with pancreatic/renal kallikrein (hK1) and
glandular kallikrein (hK2). PSA is also known as hK3. The PSA gene has
been extensively characterized (197). The 5'-untranslated region
contains regulatory elements, two of which are androgen response
elements (ARE I and ARE II), and the other is a strong enhancer (198, 199). PSA gene transcription in the prostate is known to be regulated
by androgens through the action of the AR (197-200) (Table 2). In seminal plasma, in which PSA is
present at very high amounts (1-2 g/liter), it appears that the role
of PSA is proteolytic cleavage of the sperm motility inhibitor
semenogelin, resulting in semen liquefaction post ejaculation (193, 194, 201). However, other substrates for PSA have been proposed
including insulin-like growth factor binding protein 3 (IGFBP-3) (202),
protein C inhibitor (203), transforming growth factor-ß (TGF-ß)
(204), PTH-related peptide (205), and an unknown precursor protein that
releases a putative vasoactive peptide (206). In male serum, PSA is
present as a complex with 1-antichymotrypsin (PSA-ACT),
2-macroglobulin (PSA-A2M), and as free PSA (207, 208).
|
5,000 µg/liter; about
1,000-fold higher than normal male serum). We found reduced levels of
PSA in nipple aspirate fluid obtained from women who are either at high
risk or have breast cancer (227). These data provide evidence that PSA
may have some value in assessing breast cancer risk.
PSA has also been detected in the milk of lactating women (228) or
women with prolactinoma (our unpublished data), in breast cyst
fluid (229), and amniotic fluid (230). In female serum, PSA is present
at levels approximately 1,000-fold lower than male serum (231). We
failed to find any association between total serum PSA and
clinicopathological features of breast cancer (232). However, PSA in
serum increases during pregnancy (233). More recently, we were able to
determine the molecular forms of PSA in female serum and concluded
that: 1) in serum of normal women or women without breast pathology
(e.g., hirsute women), the predominant form is always
PSA-bound to 1-antichymotrypsin (PSA-ACT); 2) in presurgical sera
from breast cancer patients, about half of them have free PSA as the
major molecular form. Similar data were found for women with benign
breast diseases (Ref. 234 and unpublished results). These data
suggest that serum-free PSA, which is an enzymatically inactive form of
PSA, is overexpressed in patients with benign or malignant breast
disease. The mechanism of such changes is unknown but the data are in
contrast to changes in prostate cancer where serum PSA-ACT increases
and free PSA decreases in cancer patients in comparison to patients
with benign prostatic hyperplasia (207). Finally, we identified some
similarities between PSA expression in the breast and expression of the
BRCA1 protein, which is believed by some to be a granin (123). Thus, we
speculated that BRCA1 may be a substrate for PSA but as yet there is no
experimental evidence for this proposal (235). Furthermore, a protein
that appears to be immunologically identical to BRCA1 has been found in
seminal plasma (236).
How is PSA regulated in the breast and in breast tumors? We have evidence that PSA is up-regulated by progestins in vivo (223) and in vitro (225, 226). Similar data exist for glucocorticoids (225, 237). In vitro, androgens up-regulate PSA at levels as low as 10-11 M, similarly to progestins (226). We have also generated evidence that PSA up-regulation by androgens occurs in vivo because women with hyperandrogenic states have higher PSA than normal controls (238). Other evidence suggests that serum PSA changes during the menstrual cycle (239). The observation that some breast tumors bearing steroid hormone receptors do not produce PSA, while others that are receptor negative may produce high levels of PSA, led us to examine the sequence of all PSA exons and the 5'-regulatory region of the PSA gene in such tumors. No mutations were identified in any of the PSA exons, but we found deletions and point mutations in the 5'-flanking region in all of these tumors (240). This finding suggests that PSA expression is aberrant in at least some breast tumors.
What is the physiological role of PSA in the breast? This is currently not known but based on the proteolytic activity of PSA, we speculate that this enzyme, regulated by steroid hormones in the female breast, must act upon a substrate to release other biologically active molecules. Others have already proposed that PSA may be a regulator of growth factors, cytokines, or PTH-related peptide, but the levels of PSA tested are much higher than those found in the breast (202, 204-206). In this regard, it is of interest that breast cancer cells secrete an IGFBP-3 protease with ability to release bound insulin-like growth factor-I (IGF-I), which can then act as a mitogen to stimulate breast cancer cell proliferation (241). Since IGFBP-3 is a substrate for PSA in seminal plasma (202), a similar role for PSA in breast carcinomas could be envisaged, although no data are available to support this hypothesis. On the other hand, the sequence homology of PSA to growth factors and growth factor-binding proteins suggests that this molecule may well be a growth factor in its own right (242). Also interesting is the proposal that PSA may act upon substrates to release vasoactive peptides, which could help in the expulsion of breast secretions, such as nipple aspirate fluid and milk, paralleling the semen liquefaction function of PSA in the prostate (206). Whatever the function of PSA is, the current evidence suggests that this molecule is a marker of differentiation and good prognosis in breast diseases, especially breast cancer. It is now very clear that this molecule, which wrongfully bears the name of a prostate-specific protein, is elegantly regulated by steroid hormones and is secreted at relatively high concentrations by breast epithelial cells. Notably, only prostate cells in males and breast cells in females produce appreciable amounts of PSA, the levels in other tumors being much lower (243).
B. Apolipoprotein D (apoD)
apoD is a protein component of the human plasma lipid transport
system that was first identified and characterized by McConathy and
Alaupovic (244). This glycoprotein is mainly associated with
high-density lipoprotein particles and consists of a single polypeptide
chain of about 30 kDa that exhibits sequence similarity to members of
the lipocalin family of proteins, whose common function is to bind and
transport small hydrophobic ligands in the plasma (245) (Table 2
). The
functional role of apoD in the metabolism of plasma lipoproteins
remains elusive, but it has been proposed that it may be involved in
transport of cholesterol or cholesteryl esters (246-248). In addition,
recent studies from different groups indicate that apoD is able to bind
and transport a wide variety of ligands other than cholesterol,
including heme-related compounds (249), progesterone (250), arachidonic
acid (251), or odorant substances (252), thus extending its potential
functional significance to a number of different biological processes.
The unexpected connection between apoD and breast diseases arose after
the observation that apoD accumulates to extremely high concentrations
(1000-fold higher than in plasma) in cyst fluid from women with
gross cystic disease of the breast (250), a benign condition associated
with an increased risk of subsequent breast cancer (253, 254). The
relationship of apoD to breast pathology was further supported by the
finding of a certain type of breast carcinoma that is able to produce
and secrete this glycoprotein (255-257). Analysis of putative
correlations between apoD levels in breast carcinomas and clinical
outcome of the disease has revealed that low apoD values are
significantly associated with a shorter relapse-free and overall
survival (257). A possible explanation as to why apoD confers a
prognostic advantage to women with breast cancer is that its presence
may reflect the existence of a complete hormone receptor pathway. To
date, the hormonal stimuli potentially responsible for the expression
of apoD by breast carcinomas are unclear, but several data suggest that
androgens could play a major role in apoD overproduction. Thus, apoD is
one of the few proteins that are up-regulated by androgens in human
breast cancer cells (257-259). This stimulatory effect is blocked by
the antiandrogen flutamide, indicating that the action of androgen is
presumably mediated via an AR mechanism. Finally, apoD has been found
to be produced by either normal or tumor prostatic cells, under
androgen stimulation (260-262).
The first indication that apoD could also be a marker of steroid action in prostate cancer cells was provided by Simard et al. (260), who examined the regulation of apoD secretion by sex steroids in LNCaP cells, the most widely used in vitro model of human prostate cancer. According to their data, physiological concentrations of androgens exert a biphasic pattern of action on both apoD secretion and cell proliferation in LNCaP cells. Thus, low concentration of androgens stimulates proliferation of prostate cancer cells and inhibits apoD secretion, whereas higher concentrations of androgens increase the expression of apoD and inhibit cell proliferation. Interestingly, such an opposite action of sex steroids on apoD secretion and cell proliferation is in complete agreement with similar studies in breast cancer cells demonstrating that the action of androgens and estrogens on apoD secretion is inversely related to cell proliferation in breast cancer cells (258, 263). On the basis of these results, apoD has been proposed as a marker of hormone action in both breast and prostate cancer cells, which could be associated with inhibition of cell growth and tumor regression (262-264). This potential value of apoD as a marker of growth arrest, together with its specific pattern of hormone responsiveness in both breast and prostate cancer cells, may be of interest from the clinical point of view. Thus, quantitation of intratumor apoD values could help to identify subgroups of breast or prostate cancer patients with low or high risk for recurrence or death, and who could benefit from specific hormone therapies.
C. Zn-2-gp
Zn-2-gp was originally isolated from human plasma,
and its name was derived from its ability to be precipitated by zinc
acetate, its electrophoretic mobility in the 2-region of
the plasma globulins, and its high carbohydrate content (265). Amino
acid sequence analysis of the protein purified from plasma has revealed
that it consists of a single polypeptide chain of 276 amino acids with
a high degree of similarity to class I antigens of the major
histocompatibility complex (MHC) (266) (Table 2). The isolation and
characterization of cDNA and genomic clones for human
Zn-2-gp have provided additional information on the
relationship between this protein and transplantation antigens
(267-269). Thus, the exon-intron organization and nucleotide sequence
of the Zn-2-gp gene are very similar to those of the
first four exons encoding the signal peptide and the three
extracellular domains characteristic of all class I MHC molecules.
However, the Zn-2-gp gene lacks the coding information
for the transmembrane and cytoplasmic domains present in class I MHC
genes, which explains its presence as a soluble protein in several
human body fluids (270). The biological function of
Zn-2-gp is unknown but, according to its structural
properties, this glycoprotein may play a role in the immune response as
a soluble HLA adapted to bind and transport some nonpolymorphic
substance in the plasma (271).
The potential interest of Zn-2-gp in relation to breast
cancer has arisen after the observation that, similar to apoD, this
soluble HLA-like protein is accumulated at high concentrations in
breast cyst fluid from women with gross cystic disease of the breast
(255, 256). Furthermore, analysis of breast cancer tissues and
secretions has revealed the existence of a significant percentage of
mammary tumors (40%) that produce and secrete appreciable amounts
of Zn-2-gp (255, 256, 272-275). Interestingly, and also
in agreement with data regarding apoD, higher levels of
Zn-2-gp were detected in histopathologically well
differentiated tumors than in moderately or poorly differentiated
tumors (273, 275), suggesting that this protein may be a marker of
tumors with high degree of differentiation, low metastatic potential,
and therefore with favorable clinical outcome. Analysis of the
molecular mechanisms controlling Zn-2-gp expression in
breast cancer cells has also provided interesting parallelisms between
this protein and apoD (259, 276, 277). Chalbos et al. (276)
were the first to observe that this protein can be induced by androgens
in T-47D breast cancer cells. These results were subsequently confirmed
and extended by Haagensen et al. (259) and López-Boado
et al. (277), who demonstrated that androgens and also
glucocorticoids up-regulate Zn-2-gp mRNA levels and
protein secretion in breast cancer cells in culture.
The possibility that Zn-2-gp could also be relevant to
prostate cancer was first suggested by Frenette et al.
(278), after their finding that the major 40-kDa glycoprotein from
human prostatic fluid is identical to Zn-2-gp. Analysis
of intraprostatic levels of Zn-2-gp in prostatic
diseases including prostate cancer revealed that these values are
strikingly higher in benign prostatic hyperplasia than in
adenocarcinomatous prostates, probably reflecting the dedifferentiation
of cancerous prostates with the loss of secretory activity. These
results agree with other studies showing that levels of other relevant
prostatic proteins such as PSA and prostatic acid phosphatase
are significantly decreased in prostatic tumors (262, 279). Further
immunohistochemical studies have confirmed the partial loss of
Zn-2-gp expression in prostatic tissue after malignant
transformation (280). In fact, Zn-2-gp was present in
benign hyperplastic glands in 91% of cases, but in only 41% of poorly
differentiated prostatic adenocarcinomas, 48% of well differentiated
adenocarcinomas, and 8% of metastases. The relationship between
Zn-2-gp and hormonal responsiveness of prostatic cancers
is not known, and further studies are required to search for a
correlation between Zn-2-gp, ARs, and tumor progression.
D. Gross cystic disease fluid protein-15
Gross cystic disease fluid protein-15 (GCDFP-15), together with
the above mentioned apoD and Zn-2-gp, represents the
major protein components found in cyst fluid from women with cystic
disease of the breast (255) (Table 2). Similar to other cyst fluid
proteins, GCDFP-15 is also produced and secreted by a subset of human
breast carcinomas. The amino acid sequence of GCDFP-15, deduced from
cDNA clones isolated from a human breast cancer cell cDNA library, is
composed of 146 residues, with sequence similarity to a protein
produced in the mouse submaxillary gland (281, 282). The biological
function of GCDFP-15 remains unclear, although it has been suggested
that it could modulate the immune response during tumor progression or
viral infection by interfering with the functions mediated by CD4 in
antigen presentation (283, 284). In addition, GCDFP-15 can exert
mitogenic activity on breast cancer cell lines and on immortal mammary
cells, but not on colon cancer, neuroblastoma, and small-cell lung
carcinoma cell lines (285). Finally, the finding that extraparotid
glycoprotein, a salivary protein identical in sequence to GCDFP-15, can
bind to oral bacteria has suggested that this protein may be involved
in modulating the colonization by bacteria in many biological fluids
(286).
Studies on the distribution of GCDFP-15 in human tissues have shown
that this protein is a normal constituent of all apocrine glands, being
also present in cells of the mammary gland that have undergone apocrine
metaplasia (287). This observation has suggested that GCDFP-15 could be
a sensitive and specific marker for monitoring and defining apocrine
differentiation in breast cancer. Studies directed to examine the
presence of GCDGP-15 in breast carcinomas and its potential
relationship to functional apocrine differentiation have shown that a
significant percentage of breast carcinomas, likely showing apocrine
differentiation, produce this protein (288). Interestingly, and also
similarly to apoD and Zn-2-gp, tumors producing GCDFP-15
have a favorable clinical outcome, when compared with those lacking
this protein (288, 289). Analysis of the mechanisms controlling
GCDFP-15 expression has also revealed an interesting parallelism with
those regulating the other major breast cyst fluid proteins (Table 2).
Thus, androgens and glucocorticoids up-regulate GCDFP-15 mRNA levels
and protein secretion in ZR-75-1 and T-47D breast cancer cells, whereas
estrogens have a marked inhibitory effect on these parameters (290).
Progestins also have a stimulatory effect on GCDFP-15 secretion by
breast cancer cells, but their effects seem to be principally mediated
by AR (276). These data, together with observations that
fluoxymesterone, a synthetic androgen, increases the plasma
concentration of GCDFP-15 in patients with metastatic breast cancer
(291), and the finding of a correlation between GCDFP-15 production and
AR levels within breast tumors (292), strongly suggest that synthesis
and release of GCDFP-15 are mainly under androgenic control. Molecular
cloning of the promoter region of the GCDFP-15 gene has revealed
the presence in its 5'-flanking region of four half-TGTTCT sequences
that could mediate this androgenic response, but no functional analysis
of this sequence has as yet been reported (282).
The first indication that GCDFP-15 could also be relevant to prostate
function resulted from the finding that the amino acid sequence of an
actin-binding protein present in human seminal plasma was identical to
that of GCDFP-15 (293, 294). In addition, an analysis of the expression
of GCDFP-15 in tumors from different origins revealed that in addition
to mammary carcinomas, the major tumor types that expressed GCDFP-15
were carcinomas of prostate, salivary glands, and sweat glands, all of
them being androgen dependent (295). Therefore, and although further
studies will be required to evaluate its clinical significance in
prostate cancer, GCDFP-15 may be added to the list of proteins
produced by both breast and prostate cancers, under similar hormone
control. On this basis, GCDFP-15, together with apoD,
Zn-2-gp, and PSA, may have potential usefulness as a
biochemical marker of a specific subset of hormone-responsive tumors
essentially driven by androgens and clinically characterized by a
favorable outcome.
E. Pepsinogen C
Pepsinogen C is the precursor of pepsin C, an aspartyl proteinase
that is mainly synthesized in the gastric mucosa and secreted into the
gastric lumen where it is converted to the corresponding active enzyme
under acidic conditions (296, 297). Pepsinogen C, also known as
progastricsin, is widely distributed in the gastrointestinal tract and
in some species, such as rodents, constitutes the major proteolytic
enzyme present in gastric fluid (298). Isolation and characterization
of cDNA and genomic clones for human pepsinogen C have shown that this
protein is composed of a single polypeptide chain of 488 residues, with
significant sequence similarity to other aspartyl proteinases, such as
pepsinogen A, procathepsin D, procathepsin E, and prorenin (299, 300).
The relationship of pepsinogen C to human breast pathology, including
breast cancer, was suggested after the finding that pepsinogen C is a
major proteolytic enzyme in the cyst fluid from women with gross cystic
disease of the breast (301). Further studies indicated that a
significant percentage of breast carcinomas (30%) have the ability
to synthesize and secrete this proteolytic enzyme (302). These
observations, together with the absence of pepsinogen C in normal
resting mammary gland, raised the possibility that this proteinase
might be involved in the lytic processes associated with invasive
breast cancer lesions, as described for other enzymes such as matrix
metalloproteinases, plasminogen activators, or secreted lysosomal
enzymes (303). However, clinical studies demonstrated that this
preliminary hypothesis was wrong. In fact, analysis of the putative
relationship between intratumor pepsinogen C levels and clinical
outcome of the corresponding patients have shown that pepsinogen C
production by breast cancer cells is associated with lesions of
favorable evolution (304). A possible explanation for this unexpected
finding is that extragastric expression of pepsinogen C may only be a
consequence of the hormonal alterations presumably involved in the
development of breast tumors, without having any direct effect on the
spread of cancer. In fact, recent studies on the hormonal regulation of
pepsinogen C in breast cancer cells have revealed that androgens,
glucocorticoids, and, to a lesser extent, progesterone, are able to
induce the expression of this gene in different breast cancer cell
lines, including T-47D, MFM-223, SK-BR3, and ZR75-1 (305). The
pepsinogen C pattern of hormone responsiveness is similar to that of
genes encoding PSA, apoD, Zn-2-gp, and GCDFP-15,
suggesting that all of them share common regulatory mechanisms that
could be responsible for their expression in some breast carcinomas, as
well as for the accumulation of their encoded proteins in pathological
breast fluids (Table 2).
In relation to the molecular mechanisms mediating the expression of these genes associated with breast cancer, it is of interest that recent functional analysis of the promoter region of the human pepsinogen C gene has led to the identification of a 15-bp cis-acting element that plays a major role in the observed pepsinogen C induction by steroid hormones in breast cancer cells (305). The nucleotide sequence of the identified hormone-responsive element (AGAACTattTGTTCC) closely resembles the consensus sequence for DNA binding of androgen, glucocorticoid, and progesterone receptors ((G/A)GAACAxxxTGTTCT), including the four major guanine/cytosine contact points for receptor binding (306, 307). Despite the similarity in their response elements, it is clear that androgens, glucocorticoids, and progesterone display distinct physiological activities. To date, the relative importance of the in vivo hormonal factors controlling pepsinogen C production in breast cancer is unclear. Nevertheless, and although the possibility that pepsinogen C expression may be under multihormonal control cannot be ruled out, several data indicate that androgens could be the most relevant steroid hormones involved in its expression by breast carcinomas. Thus, there is a close correlation between androgen inducibility of pepsinogen C expression and AR status of breast cancer cells (305). In addition, pepsinogen C is accumulated in cyst fluid from women with gross cystic disease of the breast, a pathological entity proposed to be linked to androgen dysfunction (253, 255). Finally, several groups have demonstrated that normal prostate and prostatic carcinomas are able to produce pepsinogen C (308-310). In this regard, it is noteworthy that the nucleotide sequence of the hormone-responsive element identified in the promoter of the pepsinogen C gene is strikingly similar to two elements (AGCACTtgcTGTTCT and AGCACTtggTGTTCC) that confer androgen responsiveness to the genes coding for PSA and glandular kallikrein, two serine proteinases expressed at high levels in human prostate (197, 198, 311, 312). Taken together, these results indicate that pepsinogen C, by virtue of its overproduction in breast and prostate tumors, and its specific pattern of hormone responsiveness in cultured cells, could be added to the list of biochemical markers common to both carcinomas.
F. Other proteins
The list of biomarkers that are expressed in prostate and breast
tissues is increasing. Prostate-specific membrane antigen was
widely considered to be a specific marker of prostate carcinomas until
we demonstrated its expression in breast tumors (313). The supposedly
prostate-specific glandular kallikrein (hK2), which activates PSA by
proteolytic digestion (314), has been found in the breast carcinoma
cell line T-47D, and its expression is regulated by steroid hormones in
a fashion similar to PSA (315). Liu et al. (316) have
identified a novel serine protease-like gene, the expression of which
is down-regulated during breast cancer progression, a situation similar
to all other proteins mentioned above. This gene, NES-1 (normal
epithelial cell-specific), is also expressed in the prostate and some
other tissues. Its hormonal regulation is still unknown. Another serine
protease of the kallikrein gene family has been cloned recently by
Anisowicz et al. (317). This protein (protease M) is
expressed in mammary and ovarian cancer cells as well as in prostate.
Strikingly, protease M is down-regulated in metastatic breast cancer,
in comparison to primary tumors, and may be a marker of aggressiveness.
The hormonal regulation of protease M is unknown. This recent
literature indicates that the number of biomarkers that are expressed
in breast and prostate cancer will likely increase in the near future.
Studies on hormonal regulation of these genes will be required before
they can be included among the biochemical features that can help to
establish connections between both carcinomas.
|
VI. Growth Factors in Breast and Prostate Cancer |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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, or IGF (3, 318, 319). Therefore, in this
review we focus on androgen-induced growth factor (AIGF) and
keratinocyte growth factor (KGF), which may be especially relevant in
the context of potential associations between breast and prostate
cancer (Table 2). However, it is tempting to mention a provocative new
study that has shown that elevated serum levels of IGF-I are associated
with increased risk of developing prostate cancer (320). Similar
studies are now underway to determine whether a higher risk exists for
breast cancer in women whose serum IGF-I levels are elevated.
Interestingly, preliminary observations suggest an increased risk in
premenopausal women (321, 322).
A. AIGF
AIGF was originally isolated by Tanaka et al. (323)
from the conditioned medium of androgen-stimulated mouse mammary
carcinoma cells SC-3. Isolation and characterization of cDNAs encoding
this protein have revealed that it is composed of 215 amino acids,
which share significant sequence similarity with members of the FGF
family, AIGF being the eighth identified member of this family (FGF-8).
More recently, the gene encoding the human homolog of AIGF has been
cloned and characterized (324). The amino acid sequence derived from
these genomic clones has revealed that human AIGF is completely
identical in sequence to its murine counterpart. This extreme
conservation in the amino acid sequence of AIGF in different species
suggests a highly conserved and important function. In fact, recent
studies performed by different groups have shown that AIGF plays an
important role in embryonic development, especially in gastrulation,
limb, and facial morphogenesis and brain development (325-329). In
addition to this proposed in vivo function of AIGF as a
signaling molecule involved in developmental processes, in
vitro studies have shown that this growth factor also exhibits
oncogenic properties (330). Thus, NIH3T3 cells stably transfected with
an AIGF expression vector have the abilities of tumor formation in nude
mice, focus formation in monolayer culture, and colony formation in
soft agar. It has also been demonstrated that AIGF exerts its
transforming activity through an interaction with FGF receptor-1 (330).
Analysis of the mechanisms controlling the expression of the AIGF gene in SC-3 mammary cancer cells has shown that the level of AIGF mRNA is undetectable in androgen-unstimulated cells but it is markedly up-regulated in response to physiological concentrations of testosterone. Glucocorticoids also induce AIGF expression but at much lower levels than androgens, whereas estrogens do not show any significant effect on AIGF expression (331). These results are in parallel to those on steroid hormone-induced growth of SC-3 cells. Very recent studies have also provided evidence that AIGF is induced by androgens in human breast cancer cells (332). In addition, experiments designed to directly evaluate the role of AIGF in mediating androgen-induced growth have shown that this growth factor has indeed a remarkable stimulatory effect on proliferation of SC-3 cells in the absence of androgen (331). Finally, inhibition of the translation of AIGF mRNA by specific antisense oligonucleotides is accompanied by a complete block of androgen-induced DNA synthesis (330). These observations have led to the conclusion that the androgen-dependent growth of SC-3 mammary carcinoma cells is mediated by AIGF through an autocrine mechanism. In fact, AIGF was the first sex hormone autocrine-induced growth factor structurally characterized, thereby providing definitive support to the proposals that growth factors mediate hormonal action on the proliferation of hormone-responsive cancers.
Since AIGF has oncogenic and androgen-inducible properties in mammary carcinoma cells, it was likely that this mitogen could also play a local role on the growth of the androgen-responsive prostate cancer. Several studies have shown that AIGF is expressed in the prostate cancer cell lines LNCaP and PC-3, under both testosterone-stimulated and nonstimulated conditions, suggesting that its dependence on androgens is not as strict as in mammary cancer cells (324, 333). In addition, recombinant AIGF markedly stimulated the growth of LNCaP cells, which suggests that AIGF could be part of an autocrine loop in prostate cancers, in a similar way to that proposed in mammary cancer cells (324). Consistent with this hypothesis, analysis of AIGF expression in human prostatic carcinomas has revealed a significant up-regulation of its mRNA levels in these tumors, and particularly in those corresponding to the high-grade subgroup (334). By contrast, none of the examined cases of benign prostatic hyperplasia expressed significant levels of AIGF. In summary, and although further analysis of the clinical and biological relevance of AIGF expression in breast and prostate carcinomas will be required, the present data suggest that this growth factor may play important roles in the progression of these two hormone-sensitive cancers. It will also be of interest to examine whether abnormal expression of AIGF or utilization of the different isoforms reported for AIGF may contribute to progression to hormone insensitivity in both breast and prostate cancer.
B. KGF
KGF, also known as FGF-7, is a member of the fibroblast growth
factor family consisting of 194 amino acids with a calculated molecular
mass of 24 kDa (335). KGF is exclusively produced by mesenchymal and
stromal cells of different organs and has a potent mitogenic activity
on epithelial cells that express the KGF receptor, a splice variant of
FGF receptor-2 (336). Because of this distinctive pattern of
fibroblast production and epithelial response, KGF has attracted much
interest as a paracrine mediator of stromal-epithelial interactions,
which are considered critical in many processes occurring during normal
development and malignant transformation in both prostate and mammary
gland (337).
The putative relevance of KGF in relation to prostatic function was first described by Yan et al. (338). These authors found that expression of KGF mRNA in stromal cells from normal rat prostate and rat prostate tumors is androgen-responsive, suggesting that KGF mediates the indirect control of epithelial cell proliferation by steroid hormones in this organ. The possible role of KGF in androgen-driven development has been further examined by in vitro organ culture experiments. Administration of a KGF-neutralizing antibody to the culture medium of in vitro grown newborn mouse seminal vesicles and rat ventral prostates caused a striking inhibition of both organ growth and epithelial branching morphogenesis (339, 340), supporting the idea that KGF has a major role during development of androgen-dependent organs. Recent functional studies involving the promoter region of the rat KGF gene have provided additional support to the concept that KGF acts as an andromedin in the development of male accessory sex glands. Thus, it has been described that the rat KGF promoter activity is regulated by androgens in prostate cancer cells (341). A search for the nucleotide sequence corresponding to this promoter segment has revealed the presence of several half-sites of the consensus HRE, but not a complete HRE that could mediate the observed KGF induction by androgens. Similar findings have been reported in the sequence of the human KGF promoter, suggesting that AR contributes to the control of KGF expression through these half-sites by cooperation with other transcription factors binding adjacent promoter elements (342). Finally, Thomson et al. (343) have demonstrated that antiandrogens are able to block KGF-stimulated development of the rat seminal vesicle and prostate. These results, together with the finding that KGF regulates androgen target genes in the prostate, suggest that KGF and AR signaling may interact, although in vivo evidence has not been found supporting the possibility that this growth factor is a direct mediator of androgen action (343).
KGF has not as yet been definitively associated with tumor processes, but a series of reports have suggested that aberrant expression of KGF or its receptor may be important in the development and progression of human malignancies, including prostate cancer (344-346). Thus, it has been proposed that exon switching and activation of stromal and embryonic FGF receptor genes, including KGF receptor, in prostate epithelial cells may be an event involved in progression toward malignancy (344). On the other hand, abnormal expression of KGF receptor in mesenchymal cells results in the creation of a transforming autocrine loop, which leads to the appearance of transformed foci formed by the cells expressing both KGF and its receptor (345). Also of interest is the observation that KGF can directly activate AR in the absence of androgens in prostatic cancer cells, which means that the androgen signaling chain may be activated by this mitogen in an androgen-depleted environment. This aberrant activation of the AR by KGF may therefore be one mechanism contributing to progression of prostatic cancer to an androgen-independent stage (346). Furthermore, recent studies have demonstrated significant up-regulation of KGF expression in hormone-resistant prostate cancer, while KGF expression was not detected in benign prostatic hyperplasia (347). Finally, functional assessment of human recombinant KGF in a proliferation assay demonstrated a mitogenic effect of up to 100% on cultured prostatic epithelial cells, while other growth factors such as FGF-2 did not have any effect (347).
The finding that KGF expression by stromal cells is hormonally regulated in normal and tumor prostatic cells has prompted studies directed to delineate its possible role in other hormone-dependent organs such as the human breast in both normal and pathological conditions. Consistent with this idea, it has been reported that, similar to observations in other tissues, KGF is expressed in human mammary stromal cells but not in epithelial cells (348). Also similar to other tissues, KGF receptor mRNA was present in all analyzed human mammary epithelial cell strains, but in none of the mammary stromal cells. Subsequent analysis of temporal and spatial expression of KGF during mouse mammary gland development has revealed that KGF is expressed in stroma during the ductal phase of mammary development as well as in mammary preneoplastic cells, tumor cells, and immortalized cell lines, although at lower levels than those seen during normal mammary growth (349). On this basis, it has been suggested that KGF could also be an important paracrine growth factor in the mammary gland. In fact, addition of exogenous KGF to mammary epithelial cells strongly stimulates their proliferation (350). In addition to these in vitro experiments, KGF has also been shown to be a potent growth factor for mammary epithelium in vivo. Thus, intravenous injection of KGF in rats was found to cause a dramatic proliferation of mammary epithelium in their mammary glands that was rapidly reversible after cessation of KGF treatment (351). Similar studies performed in mice have revealed that the proliferative effects of KGF are even more prominent than in rats, causing a striking cystic dilation in the mammary glands, which is histologically similar to that of fibrocystic disease in the human female breast (352). This observation raises the interesting possibility that KGF could also play a role in the development of human gross cystic disease of the breast. It is also remarkable that the mammary epithelium of lactating rats is resistant to the proliferative action of KGF, which may be of importance in relation to epidemiological observations showing that pregnancy in women decreases susceptibility to breast cancer. Finally, Kitsberg and Leder (353) have recently reported that transgenic mice carrying the KGF gene under the control of the mouse mammary tumor virus promoter develop a severe mammary and prostatic hyperplasia and mammary adenocarcinomas.
Based on these effects of KGF in rodents, it seemed likely that KGF could also play a role in the aberrant proliferation of mammary epithelial cells occurring during breast cancer progression. Consistent with this idea, Koos et al. (354) reported the presence of KGF in 12 of 15 breast carcinomas. An additional study has detected amplification of the KGF receptor gene (also called bek gene) in breast carcinomas (355) although no data are available on the possibility that amplification of this receptor is a prognostic indicator as shown for other receptors amplified in breast cancer such as HER-2/neu (50, 52). Bansal et al. (356) have confirmed and extended these studies concerning expression of KGF and KGF receptor in human breast cancer. They have observed that the expression of this androgen-induced growth factor and its high affinity receptor FGF receptor-2-IIIb is usually retained in breast carcinomas. This observation is in marked contrast to the case of other growth factors such as FGF-1, -2, -3, and -4, which are not expressed or are produced at very low levels in these tumors, and suggests that KGF may influence the progression of breast cancer through stimulation of cell division. Therefore, and although much more information is required at both basic and clinical levels, the presence of KGF mRNA in normal mammary gland and in breast tumors, together with its potent proliferative effect, suggests that KGF may be a paracrine growth factor important in the control of proliferation of normal and neoplastic mammary epithelium. In summary and on the basis of cellular localization, hormonal regulation, and biological activities, KGF may be added to the increasing list of growth factors with potential roles in the progression of prostate and breast carcinomas.
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VII. Theories of Breast and Prostate Cancer Development: Role of Steroid Hormones |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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Despite the extraordinary wealth of literature on breast and prostate cancer, their pathogenesis is still not well understood. Familial breast cancer, which accounts for about 5% of all breast carcinomas, is due to mutations of a few genes, two of which have already been cloned (69, 121). Similarly, a familial prostate cancer gene, responsible for about 5% of all prostate cancers, has been mapped to chromosome 1 but not as yet cloned (184, 357). In addition, the existence of other prostate cancer-susceptibility loci has been recently proposed (358). Nevertheless, the familial breast and prostate cancer genes do not appear to play a major role in the sporadic forms of these diseases. In the absence of any other direct genetic leads, alternative models for breast and prostate cancer pathogenesis have been developed.
Epidemiological studies conducted by many different groups over the last 40 yr provided strong evidence that the pathogenesis of breast and prostate cancer is linked to the endogenous sex steroid hormones. Any model that describes breast or prostate cancer pathogenesis must be able to accommodate the unequivocal epidemiological knowledge that has been accumulated. In the following paragraphs, we will attempt to briefly review the epidemiological evidence and then describe models for breast and prostate cancer pathogenesis. Many authors have already proposed such models, and the features described previously will be synthesized in an attempt to present a more or less integrated model for both cancers.
Breast cancer. If hormones are so intimately linked to breast cancer pathogenesis, then groups of patients who receive exogenous sex hormones for many years should provide important information. Unfortunately, the impact of oral contraceptives and hormone replacement therapy on breast cancer remains controversial. This is in sharp contrast to the endometrial cancer situation in which estrogens are clearly inducing and progestins are clearly protecting against endometrial cancer (359, 360). The last review of the vast literature on oral contraceptives has concluded that there is a slightly increased risk of breast cancer in current users, but this risk disappears after 10 yr from cessation (361). Interestingly, women using oral contraceptive pills, when diagnosed, have less advanced cancer. The issue of postmenopausal hormone therapy and breast cancer remains controversial, but the consensus is that any impact is unlikely to be great (362-365). Since these exogenously administered hormones are given after the age of 18 yr, well after puberty, it is reasonable to assume that the major changes in the breast that predispose to breast cancer may have originated earlier in life (see also below).
A few other pieces of epidemiological data are also important. Women are at a 100-fold higher risk for developing breast cancer than men. This may underline, among other possibilities, the importance of either the cycling changes of steroid hormones during the menstrual cycle, the estrogen/progestin dominance over androgen, or the protective effect of androgen. Also, it is clear that the rate of increase of breast cancer incidence slows down significantly after menopause (366). This finding is one of the most compelling in implicating ovarian steroids in the pathogenesis of breast cancer. Other important findings implicating sex steroids include the increase in breast cancer incidence associated with early age of menarche and late age of menopause (1). An even more direct effect is seen with bilateral oophorectomy, which reduces the risk of breast cancer, and the protection is greater the earlier the ovaries are removed before menopause (1, 366).
Studies of migrants have clearly demonstrated that breast cancer is not
exclusively due to genetic factors. Women who live in low-risk areas
(e.g., Japan) do not increase their risk after moving to
high risk areas (e.g., United States). The risk increases to
that of the native population by the third generation (367). The
environmental factor most intensely studied is diet. Although the issue
is controversial, many believe that high-fat, low-fiber, high-energy
food, especially if consumed early in life, may increase the risk (22, 41, 368, 369). The link between diet and breast cancer may be the serum
sex hormone levels. Although the comparison of various serum and
urinary hormone levels between patients and controls provided equivocal
results (48, 370), other studies have demonstrated reductions in
estrogen levels after dietary modifications (371, 372). Most studies
favor the view that serum estrogen levels are lower in the low-risk
groups (e.g., Japanese or Chinese women) in comparison to
high-risk groups (e.g., American or British women)
(373-375). Recently, increased emphasis was given not only to the
steroid hormones themselves but also to their metabolism. Fishman
et al. (376, 377) reviewed the evidence linking increased
C16 -hydroxylation of estradiol and the abnormal estrogen
conjugation and increased cancer risk. On the other hand, Michnovicz
et al. (378) showed that oral indole-3-carbinol treatment in
humans induces estrogen 2-hydroxylation which, in turn, results in
decreased concentrations of several metabolites known to activate the
estrogen receptor.
Among the newer observations and proposals regarding breast cancer pathogenesis, the issue of prenatal-perinatal exposures appears to be important. Trichopoulos and co-workers (379, 380) hypothesized that exposure of the fetus to high levels of estrogen during pregnancy may affect future breast cancer risk; the higher the exposure, the higher the risk. This proposal has not as yet been tested epidemiologically since it will require many decades of investigation, but there is some indirect support from studies of cerebral asymmetry and breast cancer risk (381). The importance of early events in life and their connection to future breast cancer risk have been reviewed recently (382). It appears that breast cancer prevention programs should shift the focus to adolescent years. Rat models of breast cancer indicate that exposure to high fat (primarily in the form of n-6 polyunsaturated fatty acids) and/or estrogens during pregnancy increases the risk of developing breast cancer in the offspring (383, 384). Similarly, prostate cancer risk in rodents is increased upon exposure of the fetus to small doses of estrogens, but the risk is decreased if higher doses are used (385). Human studies have indicated that both preeclampsia and prematurity significantly decrease prostate cancer risk, and a suggestion has been made that these effects are likely related to the correlation of these conditions with levels of steroid hormones and growth factors (386). Preeclampsia is also negatively associated with breast cancer risk (387), while high birth weight is a predictor of higher prostate cancer risk (388) and breast cancer risk (389). Later in this review we will borrow a concept proposed by Ross and Henderson (43) for prostate cancer to incorporate prenatal exposures in our model for breast cancer development. The last phenomenological clue regarding breast cancer risk comes from studies of breast structure in infants and adults. There are striking differences between breast structures in infants (390). Russo and colleagues (391, 392) reported dramatic changes in the mammary gland during puberty and adolescence. During pregnancy, complete differentiation of the glandular epithelium takes place. The changes induced by pregnancy more characteristic of differentiation than cell proliferation may confer protection against breast cancer (392, 393).
The epidemiological clues summarized above draw our attention to the
following points: 1) Breast cancer is not a purely genetic disease with
the exception of a small proportion of familial breast cancer; 2)
Environmental factors either acting alone or in association with
genetic factors are likely very important; 3) Endogenous and exogenous
sex hormones appear to be linked to the pathogenesis. The fact that
exogenous hormones have no dramatic effects suggests that the
endogenous hormonal milieu is very important especially early in life;
4) It appears that the risk is established at a very early stage,
e.g., during prenatal, neonatal, and pubertal life and is
continuously modified during the entire lifespan by pregnancy,
exogenous hormones, and lifestyle. All these considerations have been
included in the schematic diagram of Fig. 3, which was developed based on models
proposed by Adami et al. (366), Nandi et al.
(371), and Pike et al. (394), and by Ross and Henderson (43)
for prostate cancer.
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Prostate cancer. Similar to the situation in breast cancer,
prostate cancer is not purely a genetic disease with the exception of
about 5% of the familial prostate cancer cases. Work is in progress to
clone the familial prostate cancer susceptibility genes (184, 357, 358). Most of the clues regarding prostate cancer pathogenesis have
also come from epidemiological studies. There are only three well
established risk factors for prostate cancer: age, family history, and
ethnic group/country of residence. Highest incidence is seen in
African-Americans followed by white Americans. The lowest rates are
seen among Chinese and Japanese. The differences among white and black
Americans underline the genetic component of the disease. Migrant
studies have shown that there is no dramatic shift in prostate cancer
incidence after migration from a low risk (e.g., Japan) to a
high risk (e.g., United States) area. However, the risk
increases to that of the native men within a few generations. Similar
to the situation with breast cancer, it can be speculated that
environmental factors play a crucial role. Recent studies have focused
on diet where a consistent association, especially with fat, red meat,
low fiber, and levels of -linolenic acid were seen (38, 39, 43, 48).
The role of hormones and especially androgens in the pathogenesis of
prostate cancer is not disputed. The most convincing demonstration of
androgen involvement is the dramatic reduction of prostate cancer risk
in prepubertal castrates. Other studies have shown that
African-Americans have at least 10% higher circulating testosterone
levels than whites. The active metabolite of testosterone,
dihydrotestosterone, is generated by the action of the enzyme
5-reductase. Studies have shown that Japanese and Chinese men
have substantially lower 5-reductase activity than American men, and
this may account for the differences in prostate cancer incidence.
Additional risk factors for prostate cancer include vasectomy, early
first intercourse, large number of sexual partners, and history of
sexually transmitted disease (43).
It is well known that cell proliferation in the prostate is controlled
by testosterone after intracellular conversion to dihydrostestosterone
(43). There are two major peaks in prostate growth in humans. At
puberty, prostatic growth accelerates with appearance of PSA in serum
when androgen levels rise (395-397). At about the age of 50, a second
increase in prostatic growth occurs simultaneously with an increase in
the ratio of estrogens to androgens (398). Since receptors for
androgen, estrogen, and progesterone are present in the prostate (395, 399), it can be assumed that all these hormones affect prostate growth.
Among the androgenic hormones, dihydrotestosterone (DHT) is much more
potent than testosterone in mediating prostate growth since
patients with deficiency in 5-reductase enzyme possess very
small prostates that never develop prostate cancer (400). This finding
suggests that DHT but not testosterone is a major player in prostate
cancer pathogenesis and that the 5-reductase enzyme is crucial
in mediating DHT production. In addition to this widely
recognized role of androgens in prostate cancer, several studies have
indicated that estrogens, alone or synergizing with androgens, may be
relevant to the etiology of both benign prostatic hyperplasia and
prostatic carcinoma (401-404). Furthermore, recent studies have shown
that functions in the male reproductive system that were previously
ascribed to androgens are now known to be the result of estrogen action
(405). These data, together with the presence of estrogen receptors in
prostate, suggest that changes in the hormonal milieu not specifically
circumscribed to androgens and concomitant changes in the steroid
receptor profile in normal prostate with aging should be taken in
consideration in the genesis of prostate cancer.
There are four major cell types in the prostate. The acinar epithelial
cells possess AR and keratinocyte growth factor receptor and produce
PSA. These cells are the origin of the vast majority of prostate
cancers. The basal epithelial cells contain insulin-like growth factor
receptors (IGF-R), epidermal growth factor receptors, and estrogen
receptors. The smooth muscle cells express
1-adrenergic receptors (1-R) and estrogen receptor.
The prostatic fibroblasts express AR and a variety of growth factors
including insulin-like growth factor II (IGF-II) and KGF. The
5-reductase enzyme is localized in the fibroblasts (stroma) (395).
Clearly, the prostatic cells and the secreted growth factors create the
mitogenic microenvironment depicted in Fig. 4.
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-reductase determined by genetic and/or dietary life-style factors
(39). Different lines of evidence suggest that the initiating events in prostate cancer appear very early during life. We have calculated the tumor-doubling time of prostatic carcinoma cells in vivo, shortly after radical prostatectomy and subsequent follow-up of patients. Tumor-doubling times vary between 67 and 600 days. Assuming a mean volume at diagnosis of 5 x 109 tumor cells, we calculated how many years are necessary for one tumor cell to progress with constant doubling to 5 x 109 cells, provided that the tumor-doubling time is about 600 days. The time calculated is about 50 yr, suggesting that the tumor probably initiated around the time of puberty. We speculated that the initiating event in prostate cancer, and possibly in breast cancer, occurs during the abrupt and massive increase of steroid hormone production during puberty (406).
The central role of 5-reductase enzyme in prostate cancer
pathogenesis derives from its ability to regulate levels of DHT.
Recently, a mutation in the 5-reductase gene has been reported that
decreases the ability of the enzyme to convert testosterone to DHT
(407). Since this mutation is prevalent among Asians, it has been
postulated that it may be responsible for the low risk of prostate
cancer in this population. More recently, other mechanisms of
‘functional hyperandrogenism’ have been investigated, targeting the
AR as the important mediating molecule. The current status indicates
that the role of androgen in prostate cancer carcinogenesis is usually
mediated by normal, wild-type AR rather than by mutated forms (408).
However, an increasing number of AR genetic defects conferring a gain
of function upon the receptor have been described (85, 97, 101). In
addition, variant AR alleles containing variable CAG or GGC repeats
have different abilities to mediate the effects of androgens. The
hyperandrogenism and higher prostate cancer risk in blacks (Africans
and African-Americans) may be due to higher testosterone levels, higher
5- reductase activity, and AR alleles with higher activity due to a
smaller number of CAG repeats than whites (109). AR alleles with
shorter GGC repeats appear to be associated with higher risk for
prostate cancer, presumably due to higher transactivation potential in
mediating the effects of androgens. Unfortunately, it is still not
understood how the proliferating signals generated by steroid
hormones mediate genomic damage and in which genes and at which time
during a lifetime.
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VIII. Conclusions |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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In this review, we have given examples of genes that are altered in both breast and prostate cancer. These include the AR gene as well as BRCA1 and BRCA2 genes. Since the frequency of common genetic abnormalities is very low, the basis for the hypothesis of common genetic features in both cancers must be considered speculative and of a narrow scope. Nevertheless, recent findings demonstrating a significantly elevated risk of prostate cancer among carriers of BRCA1 or BRCA2 mutations (67, 68, 73, 74) have provided additional support to previous epidemiological observations describing associations between breast and prostate cancer (11-13, 16, 17, 20, 21). Among the other features that we have presented, the common biochemical alterations are of special interest. The finding of proteins overproduced or underproduced by tumors from both sources suggests that they might be regulated by similar mechanisms, although other possibilities cannot be ruled out. Thus, the dedifferentiation of steroid-responsive breast or prostate cells may uncover common developmental processes (337) and shared expression of proteins. Further studies directed to identify putative common regulatory pathways shared by the two tumors are necessary to clarify whether the finding of biochemical similarities may be relevant to the biology of these carcinomas. Notably, all five proteins identified as being commonly expressed between the two cancers are androgen regulated and appear to be good prognostic markers for breast cancer. This may imply that either androgens have some protective effect against breast cancer or that there is a subset of breast cancers that is androgen dependent and has a better prognosis than estrogen-dependent tumors. In this regard, Secreto and Zumoff (113) have suggested that hypertestosteronism is a consistent feature of breast cancer patients. We anticipate that the list of genes that are coexpressed in the breast and prostate will grow further in the future. In fact, An et al. (410) have reported the preliminary characterization of a novel gene (UC28) overexpressed in prostate and breast cancers but not in other tumors. Similarly, recent studies have shown that prostate-specific membrane antigen and prostate-specific glandular kallikrein, widely assumed to be specific prostatic markers, are also produced by breast carcinomas (313, 315), thus increasing the list of potential biochemical similarities between both tumors.
The current theories for breast and prostate cancer development attempt
to incorporate hormonal, dietary, and other factors into a common
pathogenetic framework. One emerging common idea is that hormones
appear to influence risk during the prenatal life, and they continue to
do so throughout life but especially during puberty. Clearly, we will
need more detailed descriptions on how hormones influence risk, which
are the genes involved, and whether these genes are structurally
altered or their expression is modified by environmental factors. We
hope that the common features of breast and prostate cancer that we
have highlighted (Table 3) will trigger
interest in finding more connections between these two cancers and
ultimately lead to strategies for common diagnostic procedures,
prevention, monitoring, and cures.
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Footnotes |
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1 The work done in the authors’ laboratories was supported by grants
from CICYT-Spain, Glaxo-Wellcome-Spain, EU-BIOMED-2, The Canadian
Breast Cancer Foundation, The Canadian Breast Cancer Research
Initiative, and Nordion International. 
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References |
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TopAbstractI. IntroductionII. Epidemiological Evidence...III. Incidence of Breast...IV. Genetic Abnormalities Common...V. Common Biochemical Features...VI. Growth Factors in...VII. Theories of Breast...VIII. ConclusionsReferences |
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W. Qiu, M. Zhou, M. Mazumdar, A. Azzi, D. Ghanmi, V. Luu-The, F. Labrie, and S.-X. Lin Structure-based Inhibitor Design for an Enzyme That Binds Different Steroids: A POTENT INHIBITOR FOR HUMAN TYPE 5 17beta-HYDROXYSTEROID DEHYDROGENASE J. Biol. Chem., March 16, 2007; 282(11): 8368 - 8379. [Abstract] [Full Text] [PDF]
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 S. Ollier, C. Robert-Granie, L. Bernard, Y. Chilliard, and C. Leroux Mammary Transcriptome Analysis of Food-Deprived Lactating Goats Highlights Genes Involved in Milk Secretion and Programmed Cell Death J. Nutr., March 1, 2007; 137(3): 560 - 567. [Abstract] [Full Text] [PDF]
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 L. Albanito, A. Madeo, R. Lappano, A. Vivacqua, V. Rago, A. Carpino, T. I. Oprea, E. R. Prossnitz, A. M. Musti, S. Ando, et al. G Protein-Coupled Receptor 30 (GPR30) Mediates Gene Expression Changes and Growth Response to 17{beta}-Estradiol and Selective GPR30 Ligand G-1 in Ovarian Cancer Cells Cancer Res., February 15, 2007; 67(4): 1859 - 1866. [Abstract] [Full Text] [PDF]
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 M. H. Slagter, L. J.G. Gooren, W. de Ronde, A. Soosaipillai, A. Scorilas, E. J. Giltay, M. Paliouras, and E. P. Diamandis Serum and Urine Tissue Kallikrein Concentrations in Male-to-Female Transsexuals Treated with Antiandrogens and Estrogens Clin. Chem., July 1, 2006; 52(7): 1356 - 1365. [Abstract] [Full Text] [PDF]
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 X. Chang, G. L. Firestone, and L. F. Bjeldanes Inhibition of growth factor-induced Ras signaling in vascular endothelial cells and angiogenesis by 3,3'-diindolylmethane Carcinogenesis, March 1, 2006; 27(3): 541 - 550. [Abstract] [Full Text] [PDF]
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 P. W. Parodi Dairy Product Consumption and the Risk of Breast Cancer J. Am. Coll. Nutr., December 1, 2005; 24(suppl_6): 556S - 568S. [Abstract] [Full Text] [PDF]
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 M Maggiolini, A G Recchia, D Bonofiglio, S Catalano, A Vivacqua, A Carpino, V Rago, R Rossi, and S Ando The red wine phenolics piceatannol and myricetin act as agonists for estrogen receptor {alpha} in human breast cancer cells J. Mol. Endocrinol., October 1, 2005; 35(2): 269 - 281. [Abstract] [Full Text] [PDF]
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H. H. Garcia, G. A. Brar, D. H. H. Nguyen, L. F. Bjeldanes, and G. L. Firestone Indole-3-Carbinol (I3C) Inhibits Cyclin-dependent Kinase-2 Function in Human Breast Cancer Cells by Regulating the Size Distribution, Associated Cyclin E Forms, and Subcellular Localization of the CDK2 Protein Complex J. Biol. Chem., March 11, 2005; 280(10): 8756 - 8764. [Abstract] [Full Text] [PDF]
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 Y. Nakamura, T. Suzuki, M. Nakabayashi, M. Endoh, K. Sakamoto, Y. Mikami, T. Moriya, A. Ito, S. Takahashi, S. Yamada, et al. In situ androgen producing enzymes in human prostate cancer Endocr. Relat. Cancer, March 1, 2005; 12(1): 101 - 107. [Abstract] [Full Text] [PDF]
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S. Kammerer, R. B. Roth, R. Reneland, G. Marnellos, C. R. Hoyal, N. J. Markward, F. Ebner, M. Kiechle, U. Schwarz-Boeger, L. R. Griffiths, et al. Large-Scale Association Study Identifies ICAM Gene Region as Breast and Prostate Cancer Susceptibility Locus Cancer Res., December 15, 2004; 64(24): 8906 - 8910. [Abstract] [Full Text] [PDF]
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U. Chatterji, J. E. Riby, T. Taniguchi, E. L. Bjeldanes, L. F. Bjeldanes, and G. L. Firestone Indole-3-carbinol stimulates transcription of the interferon gamma receptor 1 gene and augments interferon responsiveness in human breast cancer cells Carcinogenesis, July 1, 2004; 25(7): 1119 - 1128. [Abstract] [Full Text] [PDF]
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M. Maggiolini, A. Vivacqua, G. Fasanella, A. G. Recchia, D. Sisci, V. Pezzi, D. Montanaro, A. M. Musti, D. Picard, and S. Ando The G Protein-coupled Receptor GPR30 Mediates c-fos Up-regulation by 17{beta}-Estradiol and Phytoestrogens in Breast Cancer Cells J. Biol. Chem., June 25, 2004; 279(26): 27008 - 27016. [Abstract] [Full Text] [PDF]
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S. Catalano, L. Mauro, S. Marsico, C. Giordano, P. Rizza, V. Rago, D. Montanaro, M. Maggiolini, M. L. Panno, and S. Ando Leptin Induces, via ERK1/ERK2 Signal, Functional Activation of Estrogen Receptor {alpha} in MCF-7 Cells J. Biol. Chem., May 7, 2004; 279(19): 19908 - 19915. [Abstract] [Full Text] [PDF]
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C. A. Heinlein and C. Chang Androgen Receptor in Prostate Cancer Endocr. Rev., April 1, 2004; 25(2): 276 - 308. [Abstract] [Full Text] [PDF]
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 D. J. Schaid The complex genetic epidemiology of prostate cancer Hum. Mol. Genet., April 1, 2004; 13(90001): R103 - 121. [Abstract] [Full Text] [PDF]
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G. L. Firestone and L. F. Bjeldanes Indole-3-Carbinol and 3-3'-Diindolylmethane Antiproliferative Signaling Pathways Control Cell-Cycle Gene Transcription in Human Breast Cancer Cells by Regulating Promoter-Sp1 Transcription Factor Interactions J. Nutr., July 1, 2003; 133(7): 2448S - 2455. [Abstract] [Full Text] [PDF]
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V. Sung, W. Luo, D. Qian, I. Lee, B. Jallal, and M. Gishizky The Ste20 Kinase MST4 Plays a Role in Prostate Cancer Progression Cancer Res., June 15, 2003; 63(12): 3356 - 3363. [Abstract] [Full Text] [PDF]
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 M. Maggiolini, A. Vivacqua, A. Carpino, D. Bonofiglio, G. Fasanella, M. Salerno, D. Picard, and S. Ando The Mutant Androgen Receptor T877A Mediates the Proliferative but Not the Cytotoxic Dose-Dependent Effects of Genistein and Quercetin on Human LNCaP Prostate Cancer Cells Mol. Pharmacol., November 1, 2002; 62(5): 1027 - 1035. [Abstract] [Full Text] [PDF]
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C. V. Obiezu, A. Soosaipillai, K. Jung, C. Stephan, A. Scorilas, D. H. C. Howarth, and E. P. Diamandis Detection of Human Kallikrein 4 in Healthy and Cancerous Prostatic Tissues by Immunofluorometry and Immunohistochemistry Clin. Chem., August 1, 2002; 48(8): 1232 - 1240. [Abstract] [Full Text] [PDF]
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G. M. Yousef, A. Scorilas, L. G. Kyriakopoulou, L. Rendl, M. Diamandis, R. Ponzone, N. Biglia, M. Giai, R. Roagna, P. Sismondi, et al. Human Kallikrein Gene 5 (KLK5) Expression by Quantitative PCR: An Independent Indicator of Poor Prognosis in Breast Cancer Clin. Chem., August 1, 2002; 48(8): 1241 - 1250. [Abstract] [Full Text] [PDF]
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F. X. Gomis-Ruth, A. Bayes, G. Sotiropoulou, G. Pampalakis, T. Tsetsenis, V. Villegas, F. X. Aviles, and M. Coll The Structure of Human Prokallikrein 6 Reveals a Novel Activation Mechanism for the Kallikrein Family J. Biol. Chem., July 19, 2002; 277(30): 27273 - 27281. [Abstract] [Full Text] [PDF]
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 C L Chernicky, H Tan, L Yi, J R L. de Mola, and J Ilan Treatment of murine breast cancer cells with antisense RNA to the type I insulin-like growth factor receptor decreases the level of plasminogen activator transcripts, inhibits cell growth in vitro, and reduces tumorigenesis in vivo Mol. Pathol., April 1, 2002; 55(2): 102 - 109. [Abstract] [Full Text] [PDF]
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M. Maggiolini, D. Bonofiglio, S. Marsico, M. L. Panno, B. Cenni, D. Picard, and S. Ando Estrogen Receptor alpha Mediates the Proliferative but Not the Cytotoxic Dose-Dependent Effects of Two Major Phytoestrogens on Human Breast Cancer Cells Mol. Pharmacol., September 1, 2001; 60(3): 595 - 602. [Abstract] [Full Text] [PDF]
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 L. P. Hale, D. T. Price, L. M. Sanchez, W. Demark-Wahnefried, and J. F. Madden Zinc {{alpha}}-2-Glycoprotein Is Expressed by Malignant Prostatic Epithelium and May Serve as a Potential Serum Marker for Prostate Cancer Clin. Cancer Res., April 1, 2001; 7(4): 846 - 853. [Abstract] [Full Text]
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A. Scorilas, M. Talieri, A. Ardavanis, N. Courtis, E. Dimitriadis, J. Yotis, C. M. Tsiapalis, and T. Trangas Polyadenylate Polymerase Enzymatic Activity in Mammary Tumor Cytosols: A New Independent Prognostic Marker in Primary Breast Cancer Cancer Res., October 1, 2000; 60(19): 5427 - 5433. [Abstract] [Full Text]
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 C. Crescioli, M. Maggi, G. B. Vannelli, M. Luconi, R. Salerno, T. Barni, M. Gulisano, G. Forti, and M. Serio Effect of a Vitamin D3 Analogue on Keratinocyte Growth Factor-Induced Cell Proliferation in Benign Prostate Hyperplasia J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2576 - 2583. [Abstract] [Full Text]
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 M. Widschwendter, J. Berger, M. Hermann, H. M. Muller, A. Amberger, M. Zeschnigk, A. Widschwendter, B. Abendstein, A. G. Zeimet, G. Daxenbichler, et al. Methylation and Silencing of the Retinoic Acid Receptor-{beta}2 Gene in Breast Cancer J Natl Cancer Inst, May 17, 2000; 92(10): 826 - 832. [Abstract] [Full Text] [PDF]
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R. Lu and G. Serrero Inhibition of PC cell-derived growth factor (PCDGF, epithelin/granulin precursor) expression by antisense PCDGF cDNA transfection inhibits tumorigenicity of the human breast carcinoma cell line MDA-MB-468 PNAS, April 11, 2000; 97(8): 3993 - 3998. [Abstract] [Full Text] [PDF]
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 B. Bharaj, A. Scorilas, M. Giai, and E. P. Diamandis TA Repeat Polymorphism of the 5{{alpha}}-Reductase Gene and Breast Cancer Cancer Epidemiol. Biomarkers Prev., April 1, 2000; 9(4): 387 - 393. [Abstract] [Full Text]
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C. Guillemette, R. C. Millikan, B. Newman, and D. E. Housman Genetic Polymorphisms in Uridine Diphospho-Glucuronosyltransferase 1A1 and Association with Breast Cancer among African Americans Cancer Res., February 1, 2000; 60(4): 950 - 956. [Abstract] [Full Text]
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B. Berman, O. Ostrovsky, M. Shlissel, T. Lang, D. Regan, I. Vlodavsky, R. Ishai-Michaeli, and D. Ron Similarities and Differences between the Effects of Heparin and Glypican-1 on the Bioactivity of Acidic Fibroblast Growth Factor and the Keratinocyte Growth Factor J. Biol. Chem., December 17, 1999; 274(51): 36132 - 36138. [Abstract] [Full Text] [PDF]
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I. Sher, A. Weizman, S. Lubinsky-Mink, T. Lang, N. Adir, D. Schomburg, and D. Ron Mutations Uncouple Human Fibroblast Growth Factor (FGF)-7 Biological Activity and Receptor Binding and Support Broad Specificity in the Secondary Receptor Binding Site of FGFs J. Biol. Chem., December 3, 1999; 274(49): 35016 - 35022. [Abstract] [Full Text] [PDF]
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R. T. Prehn On the Prevention and Therapy of Prostate Cancer by Androgen Administration Cancer Res., September 1, 1999; 59(17): 4161 - 4164. [Abstract] [Full Text] [PDF]
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G. M. Yousef, C. V. Obiezu, L.-Y. Luo, M. H. Black, and E. P. Diamandis Prostase/KLK-L1 Is a New Member of the Human Kallikrein Gene Family, Is Expressed in Prostate and Breast Tissues, and Is Hormonally Regulated Cancer Res., September 1, 1999; 59(17): 4252 - 4256. [Abstract] [Full Text] [PDF]
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A. Scorilas, E. P. Diamandis, M. A. Levesque, A. Papanastasiou-Diamandi, M. J. Khosravi, M. Giai, R. Ponzone, R. Roagna, P. Sismondi, and C. Lopez-Otin Immunoenzymatically Determined Pepsinogen C Concentration in Breast Tumor Cytosols: An Independent Favorable Prognostic Factor in Node-positive Patients Clin. Cancer Res., July 1, 1999; 5(7): 1778 - 1785. [Abstract] [Full Text] [PDF]
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