Tamoxifen decreases mammary but not ovarian preneoplasia in a preclinical model of simultaneous breast and ovarian cancer progression.

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Women at increased risk for breast cancer are often also at increased risk for ovarian cancer reflecting common risk factors and intertwined etiology of the two diseases. Previously, we found that concurrent treatment with systemic 17β-estradiol (E₂) and local ovarian 7,12-dimethylbenz[α]anthracene (DMBA) will lead to early changes of mammary and ovarian cancer simultaneously in the rat. This combined breast/ovarian cancer model allows evaluation of joint prevention strategies against breast and ovarian cancer. Tamoxifen, the only FDA approved chemoprevention drug for breast cancer, has been shown to promote ovarian cysts in premenopausal women; however, its effect on ovarian cancer progression, if any, is unclear. In this study, we evaluated the possibility of tamoxifen as a dual-target prevention agent using our combined breast/ovarian cancer model. Fischer 344 rats (n=60) were hemiovariectomized at 5 weeks of age and the remaining ovary was treated locally with DMBA or vehicle. A sustained release tamoxifen or vehicle pellet (20 mg s.c.) was implanted following the ovarian surgery. Progression to mammary adenocarcinoma was induced by sustained release E₂ (1.5 mg s.c.). Rats were divided into 4 groups: group 1 (CONT) received systemic and intraovarian vehicles; group 2 (Tam) received intraovarian vehicle and tamoxifen pellet; group 3 (E₂/DMBA) received systemic E₂ and ovarian DMBA, and group 4 (Tam/E₂/DMBA) received systemic E₂, ovarian DMBA and systemic tamoxifen. Rats were sacrificed at 6 months post-treatment. Breast morphology was normal in CONT and Tam groups. CONT group also had normal ovarian histology while some rats in the Tam group exhibited surface hyperplasia and inclusion cysts in the ovary. E₂/DMBA treatment induced preneoplastic morphologies (i.e. epithelial hyperplasia, inclusion cysts, papilloma, and stromal hyperplasia) in the ovaries and hyperplasia, atypia, and ductal carcinoma in situ in the mammary gland. Tam/E₂/DMBA group had decreased preneoplasic changes in the mammary gland but not in the ovary compared to E₂/DMBA group. Immunohistochemistry showed increased proliferation (Ki-67) in the mammary glandular epithelium of E₂/DMBA rats compared to the controls, and this increase was prevented by tamoxifen treatment. Our study suggested that tamoxifen prevents early mammary but not ovarian cancer progression in the rat.