Characterization of a preclinical model of simultaneous breast and ovarian cancer progression

Women at increased risk for breast cancer are often also at increased risk for ovarian cancer, reflecting common risk factors and intertwined etiologies for both diseases. Unlike breast cancer prevention, primary ovarian cancer prevention has been impractical due to the low incidence, lack of risk and response biomarkers and difficulties in sampling ovarian tissue. Challenges in the development of ovarian cancer prevention drugs, however, may be circumvented through the development of breast cancer prevention strategies that simultaneously decrease ovarian cancer. In the present study, three commonly used mammary cancer carcinogen models [7,12-dimethylbenz[alpha]anthracene (DMBA), N-methyl-N-nitrosourea (MNU) and estradiol (E2)] were combined with local ovarian DMBA administration to induce progression to mammary and ovarian cancer concurrently in the rat. Animals were treated for 3 or 6 months, and tissue histology as well as proliferation, hormonal and inflammation biomarkers were assessed. Mammary and ovarian morphologies (measured as descriptive histology and dysplasia scores) were normal in vehicle controls. Mammary hyperplasia was observed in DMBA/DMBA (mammary carcinogen/ovarian carcinogen) and MNU/DMBA-treated rats; however, ovarian preneoplastic changes were seldom observed after these treatments. All E2/DMBA-treated rats had mammary hyperplasia, atypia, ductal carcinoma in situ and/or invasive adenocarcinoma, while 50% also developed preneoplastic changes in the ovary (ovarian epithelial and stromal hyperplasia and inclusion cyst formation). In both the mammary gland and ovary, decreased estrogen receptor alpha expression was detected, and in the mammary gland elevated Ki-67 and cyclooxygenase-2 expressions were observed. This combined breast and ovarian cancer rat model (systemic E2 treatment and local ovarian DMBA) may be useful for future dual target breast and ovarian cancer prevention studies.