The Stehlin Foundation for Cancer Research, Houston, Texas
77003
The natural hormone 17ß-estradiol (E2) induces
tumorsin various organs of rats, mice, and hamsters. In humans,
slightlyelevated circulating estrogen levels caused either by
increasedendogenous hormone production or by therapeutic doses of
estrogenmedications increase breast or uterine cancer risk. Several
epigeneticmechanisms of tumor induction by this hormone have been
proposedbased on its lack of mutagenic activity in bacterial and
mammaliancell test systems. More recent evidence supports a dual role
ofestrogen in carcinogenesis as a hormone stimulating cell
proliferationand as a procarcinogen inducing genetic damage. Tumors
may beinitiated by metabolic conversion of E2 to
4-hydroxyestradiolcatalyzed by a specific 4-hydroxylase (CYP1B1) and
by furtheractivation of this catechol to reactive semiquinone/quinone
intermediates.Several types of direct and indirect free
radical-mediated DNAdamage are induced by E2,
4-hydroxyestradiol, or its correspondingquinone in cell-free systems,
in cells in culture, and/or invivo. E2 also
induces various chromosomal and genetic lesionsincluding aneuploidy,
chromosomal aberrations, gene amplification,and microsatellite
instability in cells in culture and/or invivo and gene
mutations in several cell test systems. Thesedata suggest that
E2 is a weak carcinogen and weak mutagen capableof
inducing genetic lesions with low frequency. Tumors may developby
hormone receptor-mediated proliferation of such damaged cells.
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