Tamoxifen Prevents Premalignant Changes of Breast, but not Ovarian, Cancer in Rats at High Risk for Both Diseases

Abstract

Women at increased risk for breast cancer are at increased risk for ovarian cancer as well, reflecting common risk factors and intertwined etiology of the two diseases. We previously developed a rat model of elevated breast and ovarian cancer risk, allowing evaluation of dual-target cancer prevention strategies. Tamoxifen, a Food and Drug Administration-approved breast cancer chemoprevention drug, has been shown to promote ovarian cysts in premenopausal women; however, the effect of tamoxifen on ovarian cancer risk is still controversial. In the current experiment, Fischer 344 rats (n = 8 per treatment group) received tamoxifen (TAM) or vehicle (control) in factorial combination with combined breast and ovarian carcinogen (17beta-estradiol and 7,12 dimethylbenza[a]anthracene, respectively). Mammary and ovarian morphologies were normal in the control and TAM groups. Carcinogen (CARC) treatment induced mammary dysplasia with elevated cell proliferation and reduced estrogen receptor-alpha expression and promoted preneoplastic changes in the ovary. In the CARC + TAM group, tamoxifen reduced preneoplastic changes and proliferation rate in the mammary gland, but not in the ovary, compared with rats treated with carcinogen alone. Putative stem cell markers (Oct-4 and aldehyde dehydrogenase 1) were also elevated in the mammary tissue by carcinogen and this expansion of the stem cell population was not reversed by tamoxifen. Our study suggests that tamoxifen prevents early progression to mammary cancer but has no effect on ovarian cancer progression in this rat model.