17β-Estradiol Accelerates Tumor Onset and Decreases Survival in a Transgenic Mouse Model of Ovarian Cancer

Epithelial ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE) but often goes undetected in the early stages, and as a result, the factors that contribute to its initiation and progression remain poorly understood. Epidemiological studies have suggested that the female steroid hormones are involved in ovarian carcinogenesis and that women who use hormone replacement therapy are at increased risk of developing the disease. A novel transgenic mouse model of ovarian cancer (tgCAG-LS-TAg) was developed to examine the role of the female reproductive steroid hormones [17β-estradiol (E2) and progesterone (P4)] on the initiation, progression, and pathology of ovarian cancer. The mouse model uses the Cre-LoxP system to induce expression of the simian virus 40 large and small T antigens (SV40 TAg). After targeted induction of the oncogene in the OSE, mice develop poorly differentiated ovarian tumors, tumor dissemination to tissues within the abdominal cavity, and a subset develops hemorrhagic ascites. Treatment with P4 had no impact on the disease, but E2 altered the pathophysiology, resulting in an earlier onset of tumors, decreased overall survival time, and a distinctive papillary histology. Normal ovaries collected from mice treated with E2, but lacking expression of SV40 TAg, displayed an increase in the areas of columnar and hyperplastic OSE cells compared to placebo-treated controls. A better understanding of the mechanisms by which E2 alters the morphology of normal OSE cells and reduces survival in this mouse model may translate into improved prevention and treatment options for women using hormone replacement therapy. Exogenous 17β-estradiol causes putative preneoplastic lesions in the mouse ovarian surface epithelium and accelerates tumorigenesis in a transgenic mouse model of ovarian cancer.