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Adiposity, the Metabolic Syndrome, and Breast Cancer in African-American and White American Women

Departments of Epidemiology and Biostatistics (D.P.R., J.B.), Medicine (S.M.H.), and Pediatrics (J.B.), University of Texas Health Science Center, San Antonio, Texas 78284-7802

Correspondence: Address all correspondence and requests for reprints to: Dr. Jacques Baillargeon, Center for Epidemiology and Biostatistics, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7802. E-mail: baillargeon{at}uthscsa.edu

	Abstract

Top Abstract I. Introduction II. Obesity and Body... III. Obesity, Fat Distribution,... IV. The Metabolic Syndrome... V. Metabolic Syndrome, Type... VI. Biological Mechanisms VII. Commentary References

 
Breast cancer, the second most common cause of cancer-related deaths in American women, varies substantially in incidence and mortality according to race and ethnicity in the United States. Although the overall incidence of breast cancer among African-American (AA) women is lower than in white American women, this cancer is more common in young premenopausal AA women, and AA breast cancer patients of all ages are more likely to have advanced disease at diagnosis, higher risk of recurrence, and poorer overall prognosis. Epidemiological studies indicate that these differences may be attributable in part to variation in obesity and body fat distribution. Additionally, AA women more frequently exhibit breast cancer with an aggressive and metastatic phenotype that may also be attributable to the endocrine and metabolic changes associated with upper body obesity. These changes include both elevated estrogen and androgen bioactivity, hyperinsulinemia, and perturbations of the adipokines. Type 2 diabetes and the metabolic syndrome, which are more common in AA women, have also been associated with breast cancer risk. Moreover, each of the individual components of the syndrome has been associated with increased breast cancer risk, including low levels of the adipocytokine, adiponectin. This review explores the specific roles of obesity, body fat distribution (particularly visceral and sc adipose tissue), type 2 diabetes, metabolic syndrome, and adipocytokines in explaining the differential patterns of breast cancer risk and prognosis between AA and white American women.

I. Introduction

II. Obesity and Body Fat Distribution

III. Obesity, Fat Distribution, and Breast Cancer Risk

IV. The Metabolic Syndrome and Insulin Resistance

V. Metabolic Syndrome, Type 2 Diabetes, and Breast Cancer

A. Metabolic syndrome

B. Type 2 diabetes

C. Hyperglycemia and hyperinsulinemia

D. High-density lipoprotein cholesterol

E. Hypertension

VI. Biological Mechanisms

A. Estrogen production, androgens, and sex hormone-binding globulin (SHBG)

B. Insulin

C. Adiponectin

VII. Commentary

	I. Introduction

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CARCINOMA OF THE breast is the most commonly occurring cancer (with the exception of non-melanomatous skin cancers) in American women, and the second most common cause of cancer-related deaths (1). There are, however, variations in the incidence and mortality rates among the different racial and ethnic groups in the American population. The incidence of breast cancer among African-American (AA) women is lower than in white American women (2), although this difference is not great and is modified by age. The average annual age-adjusted incidence rate from 1996 to 2000 was 140.8 cases per 100,000 for white American women and 121.7 for AAs (2). In women younger than 40 yr, when the risk regardless of race is relatively low, breast cancer is actually more prevalent in AA women, but this gap closes in the later premenopausal years so that it has virtually disappeared by age 40–45 (Ref.3 and the figures therein). After the menopause, breast cancer risk increases in both races, but to a greater extent in white American women (3) such that the overall lifetime risk is lower in AA women.

In addition to the racial difference in breast cancer incidence, AA breast cancer patients are more likely than white patients to have an advanced stage of disease at diagnosis, and consequently they have a higher risk of recurrence after their initial treatment and a worse prognosis (4, 5, 6). At least in part, this poorer outcome is due to the more malignant behavior of the tumors, with an enhanced propensity for metastasis (4). The putative associations between obesity and breast cancer risk and prognosis have been the subject of considerable research activity for the past 40 yr or so (4, 7, 8, 9). Obesity is now a worldwide problem and, for example, although international comparisons show Asian populations to have the lowest breast cancer mortality rates internationally, these rates are undergoing rapid increases that have been ascribed to a shift toward Western dietary practices and an associated increase in the prevalence of obesity (10, 11, 12).

Despite the recognition that AA women have patterns of breast cancer risk and prognosis that differ significantly from those of white women, and that these are related to adiposity, no serious multidisciplinary attempt has been made to determine the endocrinological and metabolic mechanisms responsible for these epidemiological observations. The purpose of this article is to reexamine the reported, and complex, relationships between obesity and body fat distribution, and the related conditions of insulin resistance, the metabolic syndrome and type 2 diabetes, and breast cancer. Special attention has been paid to the variations that occur between this cancer in the white and AA segments of the population, the important differences that exist between body fat distributions in these two groups, and the associated metabolic disorders. The objective of this work was not to perform a systematic epidemiological review, but rather to provide an impetus for further research. To evaluate the current status of the fields of interest, we searched MEDLINE with keywords such as "obesity," "body fat distribution," "diabetes," "metabolic syndrome," and combinations of these with terms including "African-American women," "breast cancer," "estrogens," "androgens," and "adipokines." We then pursued articles referenced in these primary sources and the relevant citations.

The identification of risk factors for breast cancer has depended almost exclusively on studies of white women performed in North America or Europe, although more recently there have been significant contributions from Japan and other Asian countries; very few investigations have specifically addressed AA women. In fact, the majority of the reports originating from the United States do not specify the racial or ethnic composition of their study populations, but in such cases it seems reasonable to assume that they are composed very largely or exclusively of white women. We have been cognizant of this caveat when examining the pertinent publications, and where relevant we have specified the geographical origin of the study populations.

	II. Obesity and Body Fat Distribution

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The prevalence of obesity, defined in adults as a body mass index (BMI) greater than 30 kg/m², is increasing in the United States, as it is in most of the industrial and developing countries (13, 14). This change is seen in children and adolescents, male and female adults, and all racial groups. Nevertheless, AA women are particularly affected: data from the National Health and Nutrition Examination Survey (NHANES) of 1999 to 2000 showed 49.7% of AA, 39.7% of Mexican Americans, and 30.1% of non-Hispanic white women to be obese (14).

Typically, body fat locates to either the upper abdominal part of the body or to lower sites around the hips and thighs. Abdominal adiposity consists of three separate stores: the superficial sc, deep sc, and visceral components, which differ in their metabolic activity and contribute to varying degrees to the hormonal milieu. The visceral adipose tissue (VAT) depots are located in the greater and lesser omentum and the mesenteric fat, plus some retroperitoneal deposits. Increases in total body fat, VAT, and fat deposition in muscle occur with age and have been associated with insulin resistance, dyslipidemia, and risk of coronary artery disease and type 2 diabetes.

The ratio of the waist-to-hip circumference (WHR) has been the most frequently used measurement to assess body fat distribution in clinical studies, upper body, or ‘central’, obesity being represented by a high ratio. However, although it is accepted that both premenopausal and postmenopausal AA women are predisposed to a greater degree of upper body obesity than their white counterparts (15, 16), the WHR does not reflect the racial difference in body fat distribution regardless of the degree of general adiposity as reflected in the BMI (Table 1), being similar in AA and white women because of concomitant and equal increases in both the waist and hip measurements of the AA women (16, 20).

In summary, compared with white women, AA women are generally more obese, as reflected in higher body weight, BMI, and percentage of body fat; they have a greater waist circumference and higher SAT values, but similar VAT levels. It follows that for a given amount of total body fat mass AA women have less VAT than white women (19), which, as we shall see later, has implications for racial differences in both the metabolic syndrome and breast cancer risk factors.

	III. Obesity, Fat Distribution, and Breast Cancer Risk

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The associations between obesity, the body distribution of adipose tissue, and breast cancer have been reviewed extensively in recent years (Refs. 7, 8, 9 and 31, 32, 33, 34 and the references therein). Obesity, usually when defined in terms of the BMI, has been shown repeatedly to exert a modifying influence on breast cancer risk, but this differs in white and AA women. In white women, obesity is a recognized risk factor for breast cancer after the menopause (7, 8, 9), whereas in white premenopausal women there is an inverse relationship between the BMI and risk (7, 8, 9, 35), although this may apply only to those who are 35 yr of age or younger (36). For reasons that are not apparent and have not been studied to any significant degree, the situation in AA women is very different. In postmenopausal AA women, two studies did not find obesity to be a risk factor for breast cancer (37, 38), whereas a third did find a positive relationship (39); all three groups of investigators agreed that an inverse association between the BMI and premenopausal breast cancer risk does not occur in AA women. The reason for these reported differences is unknown, but it may be due to the operation of as-yet unknown adverse factors that are present more frequently in premenopausal AA women.

Both premenopausal and postmenopausal breast cancer patients who are obese are more likely to have a poor final outcome (8, 40, 41). In their study of more than 1000 premenopausal breast cancer patients, Daling et al. (40) found that women in the highest quartile of BMI were 2.5 times more likely to die of their disease within 5 yr of diagnosis compared with women in the lowest quartile. They also reported that tumors of women in the highest quartile of BMI were more likely to be estrogen receptor (ER) negative and to have a high S-phase fraction, high histological grade, high mitotic cell count, and large tumor size compared with women whose BMI was in the lowest quartile. Similarly, in a critical appraisal of 14 studies, Goodwin and Boyd (41) reported that obesity exhibited a modest but consistent association with decreased breast cancer survival.

In keeping with its higher prevalence, obesity was identified as a major contributor to the increased risk of advanced disease being present at the time of breast cancer diagnosis in AA compared with white patients; however, some degree of difference between the two racial groups also persisted after adjustment for obesity (4, 42), implying the presence of an additional factor that is independent of the body weight. The general consensus is that the influence of adiposity on breast cancer risk and outcome applies specifically to upper body obesity (Table 2). The WHR has been employed extensively to evaluate body fat distribution in epidemiological breast cancer studies. Despite its limitations, two reviews of the literature found that in most studies upper body obesity as determined by the WHR was a risk factor for postmenopausal breast cancer (8, 43). The Carolina Breast Cancer study (38), a population-based biracial case-control study, included 350 AA patients and 353 AA controls. It produced a most interesting result: although the BMI was inversely associated with premenopausal breast cancer in the white but not the AA women, a high WHR after adjustment for the BMI was associated with an increased risk in both racial groups, an effect that was statistically significant only in the premenopausal women (Table 2). A similar finding emerged from the reassessment of five cohort studies, largely composed of white women, performed by Harvie et al. (9). There was a 34% reduction in breast cancer for postmenopausal women with the lowest WHR values unadjusted for the BMI but no influence of the WHR when considered alone in premenopausal women. However, when the effect of general obesity was eliminated by adjusting for the BMI, not only was the risk effect for the WHR diminished in postmenopausal women, but in those who were still premenopausal there was now a 37% reduction in risk for those with the lowest WHRs. Harvie et al. (9) pointed out that the implication of these modifying effects is that the influence of the WHR on postmenopausal breast cancer risk is largely due to the coexistence of generalized obesity, whereas local fat accumulation with an upper body distribution (central obesity) specifically increases breast cancer risk in premenopausal women; the results obtained by Hall et al. (38) showed that these different effects apply to AA as well as white women. Whether evidence for a more potent effect of central obesity on breast cancer risk in AA women is lost when the anthropometric marker used is the WHR does not appear to have been addressed, but, as we noted earlier, the WHR failed to demonstrate the known racial difference in body fat distribution.

The WHR has also been studied in the context of breast cancer stage and prognosis. Borugian et al. (46) performed a prospective study of premenopausal and postmenopausal breast cancer patients in British Columbia, 88% of whom were white and 7% Asian, in which a high WHR was found to be associated with a poor prognosis, but only in postmenopausal women with ER-positive tumors. For reasons that are unclear, the waist circumference was not related to breast cancer mortality. A comparison of the relationships between obesity, body fat distribution, and stage at diagnosis in AA and white breast cancer patients was performed by Moorman et al. (47). The data confirmed the previous reports that AA patients were more likely than white patients to have advanced disease stage when diagnosed and to be severely obese. Furthermore, a high WHR was present much more frequently in the AA patients and was also associated with late-stage disease. A multivariate model used to assess the independent contributions of anthropometric characteristics in explaining AA women’s increased risk for later stage disease reduced the race-disease stage odds ratio by 20%. Inclusion of severe obesity (BMI, 32.2 kg/m² or higher) in the model reduced the race disparity in later disease by an additional 7.4%. The ER status was not among the variables examined in this study.

The inference has emerged from the present discussion that the adverse effect of upper body fat holds for both the increase in VAT in white women and in SAT in AA women. Published work to investigate the relationship between VAT and breast cancer risk appears to be limited to a small case-control study by Schapira et al. (48), which consisted of 40 white premenopausal or postmenopausal breast cancer patients and 40 community-based controls matched for age, body weight, and waist circumference. The VAT, SAT, and total fat areas were determined by computed tomography. The breast cancer patients were found to have 45% more VAT compared with the controls. Although this work needs to be confirmed and extended to AA women, similar data have been described for another cancer associated with adiposity. von Hafe (49) used computed tomography to measure abdominal fat in a prostate cancer case-control study of Portuguese men and found that the cases had a higher mean VAT and also a greater VAT to SAT ratio than age-matched healthy controls. The calculated prostate cancer risk associated with these indicators of visceral adiposity had odds ratios of 4.6 and 6.0, respectively.

	IV. The Metabolic Syndrome and Insulin Resistance

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The metabolic syndrome is characterized by a group of biochemical abnormalities and associated clinical conditions, not all of which are necessarily present in a given case, but which include disturbed glucose and insulin metabolism resulting in hyperglycemia and hyperinsulinemia, dyslipidemia [hypertriglyceridemia and low levels of high-density lipoprotein cholesterol (HDLC)], and hypertension (50); the metabolic lesions have the potential for progression to type 2 diabetes and atherosclerotic cardiovascular disease. The major risk factors for the syndrome appear to be abdominal obesity and insulin resistance, but no single pathogenesis has been identified, and, in fact, none may exist (51). Hyperinsulinemia is a biomarker for insulin resistance, a feature of the metabolic syndrome and a precursor of type 2 diabetes; increasing plasma insulin concentrations correlate with increases in the WHR (52) and the waist circumference and VAT (53) and inversely with the plasma HDLC (52).

Type 2 diabetes and the metabolic syndrome have both been associated with a state of chronic, low-grade, inflammation; inflammatory cytokines such as C-reactive protein may induce insulin resistance (54), and C-reactive protein has been associated with risk of atherosclerotic cardiovascular disease and myocardial infarct (55). The World Health Organization (WHO) and the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults ATP III, among others, published sets of criteria for defining the metabolic syndrome (51); these are summarized in Table 3. The WHO definition requires that type 2 diabetes, impaired glucose tolerance, or insulin resistance be present, for which insulin resistance may be determined by the homeostasis model assessment for insulin resistance (HOMA-IR) calculated from the fasting insulin and glucose values (51, 56). The NCEP ATP III stipulates five criteria, one which is a high fasting blood glucose (Table 3). More recently, the American Heart Association with the National Heart, Lung, and Blood Institute have reexamined the metabolic syndrome and the criteria for its diagnosis (51); the NCEP ATP III criteria were accepted with only minor modifications.

Ford and Giles (56) compared the prevalence of the metabolic syndrome as defined by the WHO and ATP III criteria in 8608 Americans; the participants included an almost equal number of women and men, and 3500 whites and 2372 AAs. It was determined that 25.1% of the participants had the metabolic syndrome as judged by the WHO criteria, and 23.9% as defined by ATP III, but there was a discrepancy between the two definitions when comparing AA and white women (AA women: WHO 30.5%, ATP III 26.1%; white women: WHO 20.3%, ATP III 22.7%), the higher prevalence of the syndrome in AA women being most apparent when defined by the WHO criteria, due largely to the dominance of central obesity (WHR > 0.85, and/or BMI > 30 kg/m²), which had an age-adjusted prevalence of 70.0% in the AA women but only 53.4% in the white women. Despite these issues of definition, it is generally accepted that the occurrence of the metabolic syndrome is particularly high in AA women (60).

While most studies, performed on white populations, have stressed the relationship between the VAT and insulin resistance, the SAT may play a more significant role in AA women. Marcus et al. (61) found that AA women were more insulin resistant than white women at all levels of abdominal adiposity, and that the truncal SAT deposits correlated inversely with the insulin sensitivity index; as noted earlier, AA women have greater SAT, but similar VAT depots. Thus, it appears that the VAT is less important in the development of the metabolic syndrome in AA than white women. Moreover, as pointed out by Despres et al. (19), that the VAT is lower in AA than white women relative to the total body fat mass explains, at least in part, the observed higher plasma HDLC in obese AA than obese white women.

	V. Metabolic Syndrome, Type 2 Diabetes, and Breast Cancer

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A. Metabolic syndrome
There has been very little effort to study the relationship between breast cancer and the metabolic syndrome as defined by the criteria described in the previous section, although Pasanisi et al. (62) found that the risk of breast cancer recurrence was increased in a small number of women who met the requirements for diagnosing the syndrome.

The variations in the components of the metabolic syndrome that occur between individuals, including those associated with race and ethnicity, may define different levels of risk for related chronic diseases, including breast cancer. Table 4 compares the prevalence of individual elements of the syndrome in AA and white American women and their reported association with breast cancer risk. The significance of the WHR and waist circumference as potential risk factors for breast cancer needs further consideration in the context of the metabolic syndrome. Because these anthropometric measurements are included among the criteria for the diagnosis of the syndrome, the question arises as to the extent to which they influence breast cancer risk as distinct entities, rather than providing diagnostic markers of the syndrome.

Epidemiological investigations have shown relationships between breast cancer and type 2 diabetes (Table 5). Three American prospective studies found that type 2 diabetes was associated with a modest increase in postmenopausal breast cancer risk (67, 68, 69); in two studies (67, 68), this effect was independent of age, obesity, and reproductive factors, but in the third (69) the incidence of breast cancer was 60% higher among diabetic women than among those with fasting blood glucose levels below 100 mg/dl, but with attenuation of the effect after adjustment for the BMI. Verlato et al. (70) determined the mortality risk from site-specific cancers in Italian men and women with type 2 diabetes and observed an excessive risk of death from breast cancer among the postmenopausal female patients that was confined to obese women. In Sweden, Weiderpass et al. (71) assessed the incidence of breast cancer in 80,005 women who had been treated for diabetes. For follow-up, which averaged 6.7 yr, cancers diagnosed in the first year were excluded so that there were 1145 diabetic patients who had developed breast cancer; these gave a calculated standardized incidence ratio of 1.3 with a 95% confidence interval (CI) of 1.2–1.4. This excess risk applied only to those who were aged 40 yr or older at the time of entry into the study and who consequently were most likely to have type 2 diabetes.

C. Hyperglycemia and hyperinsulinemia
In addition to clinically manifest type 2 diabetes, high fasting plasma glucose concentrations (77) and hyperinsulinemia without diabetic symptoms (77, 78, 79) have been associated with an increase in both premenopausal and postmenopausal breast cancer risk. Muti et al. (77) performed a prospective study in Italy with 10,786 women aged 35–69 yr; fasting plasma glucose concentrations were determined, and after 5.5 yr of follow-up 144 participants had developed breast cancer. Plasma glucose levels in the highest quartile vs. the lowest were associated with an almost 3-fold increase in premenopausal breast cancer risk; in postmenopausal women the relationship was weaker and did not achieve statistical significance. Lawlor et al. (80) reported on a large cross-sectional study of British postmenopausal women in whom the fasting serum insulin and glucose levels were determined. Of the 3868 women in the study, 151 had a history of breast cancer, and the insulin and glucose concentrations were both higher in this subgroup.

Elevated plasma insulin levels have also been related to disease recurrence and a poor prognosis. Goodwin et al. (81) found that in both premenopausal and postmenopausal women high fasting plasma insulin concentrations correlated with the presence of high tumor grade and axillary lymph node involvement and with an increased risk of recurrence and shortened survival. The relationship was independent of the BMI, and there was no association between the insulin levels and tumor ER status. Elevated serum concentrations of C-peptide, a subunit of insulin that provides a clinically useful indication of insulin production and the degree of insulin resistance, have been associated with an increased breast cancer risk in several case-control studies (79, 82, 83, 84, 85). Both Bruning et al. (82) and Yang et al. (83) also showed that the ratios of C-peptide to either glucose or fructosamine, an index of insulin resistance, were elevated in the breast cancer patients, and that the changes were independent of both the BMI and the WHR. It needs to be stressed that there do not appear to be any published studies in which type 2 diabetes, hyperinsulinemia, or insulin resistance have been related specifically to breast cancer risk and outcome in AA compared with white women, although as we have seen, these components of the metabolic syndrome and risk factors for breast cancer occur more commonly in AA than white American women.

D. High-density lipoprotein cholesterol
Several investigations focused attention on the serum lipoprotein patterns in breast cancer (86, 87, 88). Furberg et al. (86) carried out a 17.2-yr prospective study of 38,823 Norwegian women who were 17 to 54 yr old when serum samples were collected at entry; 708 developed breast cancer over the study period. The risk of postmenopausal breast cancer, but only for those who were overweight (BMI, 25.0 kg/m² or higher), was found to be inversely related to the serum HDLC, the risk in the highest serum HDLC quartile being one third that of women in the lowest quartile. The authors suggested that there was a synergistic effect between a low HDLC and obesity-related elevations in the serum insulin, IGF-I, and sex hormones. Michalaki et al. (87) observed the same relationship between the serum HDLC concentration and postmenopausal breast cancer in a case-control study. Han et al. (88) found that in their Chinese patients the serum HDLC levels were lower and the serum insulin, leptin, and triglyceride concentrations were higher in 130 breast cancer patients than the same number of controls. There are no published studies of serum HDLC levels and breast cancer in AA women, but this is a topic worthy of investigation; as we have seen in this review, although a low HDLC concentration is one of the criteria used for diagnosis of the metabolic syndrome, and the syndrome itself is more common in AA women, serum HDLC levels are typically higher in AA than white women and so, in contrast to white women, may not be implicated in breast cancer risk.

E. Hypertension
Hypertension occurs both as a single entity and as part of the metabolic syndrome; in both situations it is particularly common among AAs (90, 91). It has been reported to be a risk factor for breast cancer, although the effect was a weak one (92, 93). An Italian case-control study involving 3406 breast cancer cases and 3054 hospital controls found the association particularly in postmenopausal women, and it tended to be stronger in patients who were obese and/or had diabetes; nevertheless the calculated odds ratio for breast cancer risk was 1.2 (95% CI, 1.1 to 1.4) after correction for the BMI and menopausal status (92).

	VI. Biological Mechanisms

Top Abstract I. Introduction II. Obesity and Body... III. Obesity, Fat Distribution,... IV. The Metabolic Syndrome... V. Metabolic Syndrome, Type... VI. Biological Mechanisms VII. Commentary References

 
The mechanisms by which central obesity, type 2 diabetes, and the metabolic syndrome jointly promote breast cancer development are summarized in Fig. 1.

View larger version (24K): [in this window] [in a new window]   FIG. 1. The interactions between central obesity, type 2 diabetes, and the metabolic syndrome in providing the biochemical mechanisms for stimulating breast epithelial cell transformation and proliferation. A2, Androstenedione; 17-OR 1, 17-β-oxidoreductase type 1.

The level of aromatase activity is site-specific: the rate of conversion of androstenedione to estrone is high in adipose tissue associated with the buttocks and thighs (97) and therefore in women with lower (gynoid) obesity, but it is also much greater in the upper body SAT than VAT (98). Obese premenopausal white and AA women were found not to have increases in their plasma estrogens (99, 100), presumably because their extraglandular production is small relative to the amount of estrogens arising from the premenopausal ovaries. However, despite this reasonable explanation, although Barnett et al. (100) found no difference in the plasma concentrations of midfollicular plasma total and free estradiol of nonobese and obese premenopausal AA women, when account was taken of the body fat distribution, the estradiol concentrations were significantly higher in those with upper body adiposity as judged by elevations in the WHR. Pinheiro et al. (101) found that the serum total and unbound, biologically active estradiol concentrations were higher in AA compared with white premenopausal women, a result which is consistent with their greater accumulation of SAT, and consequently higher total aromatase activity, and their increased breast cancer risk. However, whereas other investigators who also assayed blood samples collected during the luteal phase of the menstrual cycle confirmed this racial difference (102), others, who assayed follicular samples, did not, and they found either similar levels in the two races (103) or lower concentrations in AA women (104). Clearly, further investigations are needed to clarify these potentially important observations and to extend them to postmenopausal women and to an in-depth analysis of breast cancer risk. In addition to the increased production of estrogens from androstenedione that occurs in obese women, the biologically available fraction of the total circulating estradiol is elevated in upper body obesity because of a reduction in the hepatic synthesis, and hence the plasma concentration, of SHBG. Estrogen bioactivity is tightly regulated with 30–50% of the plasma estradiol being strongly bound to the SHBG and in consequence rendered biologically inert. Most of the rest is weakly bound to albumin, from which it is readily dissociated, and 1–2% circulates as unbound "free" estradiol; both of these fractions are considered to be available for biological activity (reviewed in Refs. 105 and 106).

Testosterone binds to SHBG with an even greater affinity than estradiol, and, again, reduced plasma SHBG concentrations are associated with an elevation of the biologically active steroid (107). Plasma free and total testosterone concentrations are elevated in women with type 2 diabetes (108, 109) and have been associated with an increased risk of the disease in women, whereas the reverse was found to be true in men (109). In nondiabetic postmenopausal women, androgenicity, as judged by the plasma free testosterone, correlated positively with insulin resistance (110). Ivandic et al. (111) reported that for nondiabetic obese premenopausal Croatian women the plasma insulin and the free testosterone were higher in those with upper body adiposity than those with lower body adiposity, as assessed by the WHR, with concomitantly lower SHBG concentrations.

Androstenedione, which does not bind to SHBG, is secreted, largely from the adrenal glands and to a lesser extent the ovaries, in increased quantity in women with upper body obesity; consequently, more substrate is available for aromatization to produce the estrogen estrone, which can then be converted to the more biologically potent estradiol (105). In addition to providing C19 steroid precursor for estrogen synthesis, androgens have a direct role in breast tumorigenesis and may do so as part of the mechanism by which type 2 diabetes and the metabolic syndrome adversely affect breast cancer risk.

There is a substantial literature that associates high plasma testosterone concentrations with an increase in breast cancer risk. Key et al. (112) performed a reanalysis of pooled data from nine prospective cohort studies of breast cancer risk in postmenopausal women with prediagnostic assays of sex hormones and found an approximately 2-fold risk elevation between the lower and upper quintiles for the testosterone concentration; the SHBG was inversely related to risk. The European Prospective Investigation into Cancer and Nutrition Group (113) has reported a very large cohort study of postmenopausal serum androgens, estrogens, and breast cancer risk, which again confirmed that the testosterone level, together with the calculated free testosterone and dehydroepiandrosterone sulfate, was positively associated and the SHBG was negatively associated with risk. Adjusting for the BMI had essentially no effect on the relative risk estimates.

In Italy, Micheli et al. (114) carried out a prospective study of premenopausal women that provided 65 breast cancer cases after 5.2 yr of follow-up. The serum free testosterone was positively associated with breast cancer risk after adjustment for the BMI and in these premenopausal women, there was an inverse association with the progesterone concentration. Another study of premenopausal women, this one of case-control design nested in a cohort study that provided 370 cases and 726 controls, also found increased risk with higher testosterone levels as well as a significant reduction with elevated progesterone concentrations (115). We are not aware of any studies that have sought to examine androgens and breast cancer risk in the context of the metabolic syndrome or in relation to specific ethnic groups; it appears that all the reported investigations were performed on white populations.

Low plasma SHBG levels occur in conjunction with insulin resistance and other components of the metabolic syndrome in both white (116, 117) and AA (118) premenopausal women; higher SHBG levels were found to reduce the risk of type 2 diabetes, an effect that was stronger in women than in men (109). Plasma SHBG concentrations are inversely correlated with the BMI, and particularly with upper body adiposity as indicated by inverse correlations with a high WHR and waist circumference, in both premenopausal and postmenopausal white women (16, 119). In AA women, the situation is somewhat different; whereas the same negative association between the plasma SHBG and upper body obesity is present before the menopause (100), there is no relationship in postmenopausal AA women despite the high incidence of obesity (16). Moreover, premenopausal AA women have lower plasma SHBG concentrations than premenopausal white women (101), which accounts for their higher levels of circulating biologically active estrogen, whereas in postmenopausal women these levels are similar in both races (16). In results from 2961 women studied as part of the Study of Women’s Health Across the Nation project, the plasma SHBG showed a strong inverse correlation with the presence of the metabolic syndrome, which was identified in 17% of the participants (119).

Low plasma SHBG levels have been associated with an increased breast cancer risk in postmenopausal women (96, 112, 120). Toniolo et al. (96) performed a large prospective cohort study that showed that the plasma SHBG-bound estradiol was inversely related to risk, whereas the unbound ("free") estradiol fraction had a positive relationship. A reanalysis by the Endogenous Hormone and Breast Cancer Collaborative Group (112) of data from nine prospective studies also demonstrated a protective effect of SHBG in postmenopausal women and showed an increasing degree of risk with increases in the non-SHBG-bound estradiol concentration. Neither of these studies examined the data on the basis of the racial composition of the cohorts, but they most likely comprised white women very largely.

The mechanism by which obesity reduces breast cancer risk in young premenopausal white women (7, 8, 9, 35, 36), which Peacock et al. (36) found was restricted to those aged 35 yr or younger, may relate to its suppressive effect on ovarian function, with the induction of anovulatory and irregular menstrual cycles and subnormal circulating estrogen levels (8). The reason why a similar protective effect is not seen in AA women (37, 38, 39), in whom breast cancer occurs up to 10 yr earlier than in white American women (121), is unknown but could arise from ovarian estrogen production being less vulnerable to obesity-related suppression; also, a higher proportion of the breast cancers arising in premenopausal AA women may lack an estrogen requirement for their development, as reflected in the relatively high incidence of ER-negative cancers (122).

B. Insulin
One mechanism by which insulin might promote breast cancer is by causing a reduction in SHBG production (123) with a consequent elevation in bioavailable estradiol and stimulation of tumor cell proliferation. Insulin can also induce aromatase activity (124), thus producing an increase in estrogen biosynthesis that in adipose tissue or tumor cells could result in stimulation of breast cancer cell growth by endocrine, paracrine, or autocrine mechanisms. In this context, it is of interest that Michels et al. (67) reported that the relationship between type 2 diabetes and breast cancer risk in a largely white population was predominantly for ER-positive tumors. Moreover, in cell culture experiments in vitro insulin was found to stimulate the growth of ER-positive human breast cancer cells, but to have no effect on ER-negative cell lines (reviewed in Ref.125).

C. Adiponectin
Among the various hormonal factors affecting breast cancer biology are members of a family of polypeptides that are produced exclusively or predominantly by adipocytes. One of these adipocytokines, adiponectin, is proving to be of particular significance when discussing the roles of obesity and insulin resistance in breast cancer development and progression. A second, leptin, is mitogenic for breast cancer cells in vitro, and has biological activities that suggest its involvement in tumor cell angiogenesis and metastasis, as we discussed elsewhere (126), but epidemiological support for a role for circulating leptin in the etiology of this cancer in humans continues to be equivocal, as is the relationship between plasma levels and race and ethnicity, and so because further research is essential to clarify the situation it will only be touched on in this review.

Adiponectin, an antiinflammatory protein, is synthesized and secreted almost exclusively by adipocytes; its plasma concentration is inversely correlated with the BMI, the WHR, and waist circumference, and the VAT (127, 128, 129) is decreased in obesity and type 2 diabetes and is present in inverse proportion to the degree of insulin resistance (reviewed in Ref.130). Low plasma adiponectin levels have been associated with various components of the metabolic syndrome and shown to decrease as the number of components present increases (131). A prospective multicenter community study of 10,275 AA and white men and women performed in the United States demonstrated that those in the highest quartile of plasma adiponectin had a 40% lower risk of diabetes than those in the lowest quartile (132). Hypoadiponectinemia was shown to occur in association with hypertension, and although this relationship was initially considered to occur only in patients with insulin resistance, Iwashima et al. (133) subsequently reported that, at least in Japanese men, it is actually an independent risk factor and that blood pressure is inversely associated with the plasma adiponectin concentration in normotensive individuals regardless of their level of insulin sensitivity.

Hypoadiponectinemia is also associated with low plasma HDLC and high triglycerides and with decreased plasma lipoprotein lipase, which is independent of insulin resistance (134). In women with impaired glucose tolerance or frank type 2 diabetes, the plasma adiponectin concentrations were inversely correlated with the C-reactive protein levels (135); chronic inflammation has been associated with cancer development and progression as well as cardiovascular disease, and in a prospective study of 2438 participants high circulating C-reactive protein concentrations at baseline were shown to be associated with an increased breast cancer risk (136). From this brief discussion of the published work, it is clear that the circulating adiponectin levels are reduced in a number of situations, which this review has shown are associated with increased breast cancer risk (Table 5).

Two epidemiological investigations, one from Japan by Miyoshi et al. (137) and the other from Greece by Mantzoros et al. (138), demonstrated a relationship between low adiponectin levels and increased breast cancer risk that persisted after adjustment for the BMI. In the Japanese study, the adverse effect associated with hypoadiponectinemia was evident regardless of menstrual status but was stronger in postmenopausal women; it was also present regardless of tumor ER status, but the relationship was statistically more robust in the patients with ER-negative breast cancers. Mantzoros et al. (138) observed a statistically significant effect of a low plasma adiponectin on risk only in those women who were beyond the menopause, but there were only a small number in the premenopausal category; they did not comment on any influence of ER status. Miyoshi et al. (137) also observed that there were more large tumors and tumors of high histological grade, consistent with an aggressive phenotype, in the Japanese patients with serum adiponectin concentrations that were in the lowest tertile. A third study, from Taiwan (139), also found that the serum adiponectin concentrations were reduced in 100 newly diagnosed breast cancer patients compared with 100 controls. The serum leptin levels were also assayed in this study and were elevated in the cancer patients compared with the controls, although the changes were not as pronounced as the decreases in the adiponectin. There was no evidence of a relationship between the serum adiponectin levels and the tumor grade, stage, or ER status in this study, but the ratio of leptin to adiponectin in the serum was positively correlated with tumor size.

One recent report by Kang et al. (140) showed that adiponectin, when present in vitro at concentrations similar to those in human plasma, induced inhibition of growth and enhanced apoptotic activity in the highly metastatic, ER-negative MDA-MB-231 human breast cancer cell line; a second report by Dieudonne et al. (141) noted similar effects of the adipokine on ER-positive MCF-7 breast cancer cells. Adiponectin has similar growth-suppressing activity on vascular endothelial cells, which, together with inhibition of cell migration, results in inhibition of angiogenesis in in vivo models (142). Finally, in animal studies, the infusion of adiponectin into highly vascularized mouse fibrosarcomas produced suppression of tumor growth, most likely by antiangiogenic activity (142). Such biological effects are consistent with a role for adiponectin in the inhibition of breast cancer progression.

Although we have no data on adiponectin and breast cancer in AA women, the reports that have been published on the effect of race on the plasma levels are of interest. As part of the large community study performed by Duncan et al. (132) which showed an attenuation of diabetes risk in cohorts with relatively high plasma adiponectin concentrations, it was also observed that the mean adiponectin levels were 22% lower in the AA than white men and women, a result consistent with their higher risk for type 2 diabetes. This racial difference was present within groups stratified into those of normal weight, overweight, or obese on the basis of the BMI. Another study performed in the United States by Hulver et al. (143) found that the plasma adiponectin concentrations of nonobese and obese AA women and obese white women were all significantly lower than those of nonobese white women. Finally, Bush et al. (144) found that the serum adiponectin levels of AA children and adolescents of both sexes were lower than those of their white counterparts and were inversely related to the central fat mass. There are also racial differences in serum C-reactive protein levels; specifically, the concentrations of this acute inflammatory protein, which has been associated with insulin resistance, the metabolic syndrome, and breast cancer risk, are higher in AA women and men than their white counterparts (145).

	VII. Commentary

Top Abstract I. Introduction II. Obesity and Body... III. Obesity, Fat Distribution,... IV. The Metabolic Syndrome... V. Metabolic Syndrome, Type... VI. Biological Mechanisms VII. Commentary References

 
Most of the established risk factors for breast cancer have only weak effects when considered individually, and together they were calculated to account for approximately 50 to 55% of the total risk among women in the United States (145, 146, 147). Very few studies of breast cancer risk factors have focused on AA women, but the data that are available indicate that these are generally the same as those identified for white women and that it is the variation in their prevalence which is responsible for the differences in disease risk (147, 148), a conclusion that also follows from the comparisons described here. Brinton et al. (148) concluded that these factors are responsible for a smaller proportion of the total risk in AA women; from their data the number of births, age at first completed pregnancy, age at menarche, history of breast biopsy, and breast cancer family history were estimated to account for 62% of the breast cancer risk in white women aged 40–54 yr, but only 54% in AA women in the same age range. The studies discussed in this review and summarized in Fig. 1 suggest that in addition to these classical risk factors for breast cancer, type 2 diabetes, and the metabolic syndrome, hyperinsulinemia and insulin resistance in the absence of clinically evident diabetes, perhaps hypertension, overstimulation of the breast epithelium by estrogens and testosterone, and direct and indirect effects of altered adipocytokine production on mammary tissue may all add disproportionately to the risk of breast cancer in AA women, and, perhaps of even more clinical significance, to the development of an aggressive, metastatic phenotype.

The demonstration by Hall et al. (38) that in both AA and white premenopausal women the WHR, when adjusted for the BMI, was associated with an increased breast cancer risk, whereas the BMI itself was inversely related to risk only in white women, is an intriguing finding. In the meta-analysis of data from five cohort studies involving white and Asian women performed by Harvie et al. (9), the results for those who were premenopausal gave similar results: it was suggested that the mechanism for this adverse effect of a high WHR might involve the known association of the ratio with insulin resistance, to which we would add the biochemical abnormalities that are part of, or accompany, the metabolic syndrome, and which also have their own individual effects on breast cancer risk. The recent reports that overweight children frequently have hyperinsulinemia and the metabolic syndrome if child-specific criteria are applied (148, 149), and that obesity-associated type 2 diabetes is being seen in childhood with increasing frequency (150) ensure that they may act as risk factors for early-onset premenopausal breast cancer, and particularly in young AA women.

The relatively low serum adiponectin concentrations in AA children were inversely correlated with central adiposity (144), and hypoadiponectinemia, which Miyoshi et al. (137) found to associated with ER-negative tumors, may be particularly significant for AA women in whom ER-negative, estrogen-independent breast cancers are more common. Moreover, figures from the Surveillance, Epidemiology, and End Results (SEER) database showed that in premenopausal AA women the percentage of ER-negative tumors was higher than in premenopausal white women, the difference being most pronounced for the 35- to 39-yr age group at 58 and 42%, respectively (151). The relatively high incidence of estrogen-independent breast cancers in premenopausal AA women also goes at least some way in explaining why their tumors are potentially resistant to the growth suppression associated with subnormal ovarian estrogen production, a result of obesity-related anovulatory menstrual cycles.

AA patients also have a higher frequency of ER-negative tumors than white patients after the menopause (4, 152), and so one possible factor contributing to the lower risk of clinically manifest invasive breast cancer in postmenopausal AA women is that a higher proportion of carcinomas in situ fail to respond to the obesity-related elevation in circulating estrogens. More attention needs to be paid to the significance of insulin resistance and its clinical correlates in adversely affecting the risk and biological behavior of breast cancer. Although insulin resistance, the metabolic syndrome, and type 2 diabetes are typically associated with upper body obesity, as we have discussed, all three occur in its absence and particularly so in AA women. The results of studies performed in premenopausal women have separated obesity from insulin resistance as risk factors for breast cancer (78, 82). Del Giudice et al. (78), in their case-control study of Canadian nondiabetic premenopausal women found the cases to weigh less and to have a smaller BMI, consistent with obesity as a protective factor, and high plasma insulin concentrations to be positively associated with breast cancer risk after adjustment for body weight.

Obesity has a deleterious effect on breast cancer outcome regardless of menopausal status, as was confirmed by Goodwin et al. (81) in a prospective study of plasma insulin levels and the prognosis of women with early stage breast cancer. Hyperinsulinemia was seen most commonly in conjunction with increased adiposity, but this was not always the case, and the positive association of high insulin levels with disease recurrence and an increased mortality rate persisted after adjustment for the BMI. Further studies are needed with particular attention being paid to AA women, and specifically to determine the extent to which hyperinsulinemia and/or other elements of the metabolic syndrome such as hypoadiponectinemia are responsible for the reported portion of the increased risk of recurrence in AA breast cancer patients that remains after correction for obesity (42).

At present, the involvement of the metabolic syndrome per se in breast cancer risk is unclear. We have reviewed epidemiological studies that demonstrated relationships between individual components of the syndrome, notably those associated in some way with insulin resistance, and cancer risk, but there are no published data that actually show that when these entities cluster to merit the designation of a syndrome the breast cancer risk is greater than that derived from the individual elements. It is worth noting again, however, that the plasma adiponectin levels fall as the number of components of the metabolic syndrome present in an individual case increase (131).

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online November 2, 2007

Abbreviations: AA, African-American; BMI, body mass index; CI, confidence interval; ER, estrogen receptor; HDLC, high-density lipoprotein cholesterol; SAT, sc adipose tissue; VAT, visceral adipose tissue; WHR, waist-to-hip ratio.

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