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Potential mechanisms whereby estrogens induce breast cancer in women

Long-term exposure to estradiol is associated with an increased risk of breast cancer in women. The data supporting this conclusion include: measurements of plasma total and free estradiol, estrone, and estrone sulfate and the aromatase substrate testosterone in postmenopausal women; the effect of oophorectomy before age 35; the effect of early menarche and late menopause; the relationship between bone density and breast cancer risk; and the role of menopausal hormone therapy on risk. However, the mechanisms responsible for estradiol-induced carcinogenesis are not firmly established. The prevailing theory postulates that estrogens increase the rate of cell proliferation by stimulating estrogen receptor (ER)-mediated transcription, thereby increasing the number of errors occurring during DNA replication. An alternative theory suggests that estradiol is metabolized to quinone derivatives, which directly remove base pairs from DNA through a process called depurination. Error-prone DNA repair then results in point mutations. We postulate that both processes act in an additive or synergistic fashion. If correct, aromatase inhibitors would block both processes, whereas anti-estrogens would only inhibit receptor-mediated effects. Our initial studies demonstrated that depurinating catechol-estrogen metabolites are formed in MCF-7 human breast cancer cells in culture. We then utilized an ERKO animal model that allows dissociation of ER-mediated function from the effects of estradiol metabolites, and demonstrated formation of genotoxic estradiol metabolites. We also examined the incidence of tumors formed in these ERα knockout mice bearing the Wnt-1 transgene. The absence of estradiol induced by castration markedly reduced the incidence of tumors and delayed their onset. Re-administration of estradiol to castrate animals induced tumors in a dose-responsive fashion. To ensure that all ER functionality was lacking, we administered fulvestrant and demonstrated that estrogen still induced breast tumors in these animals. On aggregate, our results support the concept that metabolites of estradiol may act in concert with ER-mediated mechanisms to induce breast cancer. These findings support the possibility that aromatase inhibitors might be more effective than anti-estrogens in preventing breast cancer. Data from four clinical studies have now suggested that fewer contralateral breast cancers occur in women treated with aromatase inhibitors in the adjuvant setting than with tamoxifen. Taken together, our data provide experimental support for a genotoxic role for estradiol in hormonal carcinogenesis.

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Santen, R., Yue, W. & Wang, JP. Potential mechanisms whereby estrogens induce breast cancer in women. Breast Cancer Res 7 (Suppl 2), S.08 (2005).

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