Dysregulated Estrogen Receptor Signaling in the Hypothalamic-Pituitary-Ovarian Axis Leads to Ovarian Epithelial Tumorigenesis in Mice

摘要

The etiology of ovarian epithelial cancer is poorly understood, mainly due to the lack of an appropriate experimental model for studying the onset and progression of this disease. We have created a mutant mouse model in which aberrant estrogen receptor alpha (ERα) signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis. In these mice, termed ERα~(d/d), the ERα gene was conditionally deleted in the anterior pituitary, but remained intact in the hypothalamus and the ovary. The loss of negative-feedback regulation by estrogen (E) at the level of the pituitary led to increased production of luteinizing hormone (LH) by this tissue. Hyperstimulation of the ovarian cells by LH resulted in elevated steroidogenesis, producing high circulating levels of steroid hormones, including E. The ERα~(d/d)mice exhibited formation of palpable ovarian epithelial tumors starting at 5 months of age with 100% penetrance. By 15 months of age, 80% of ERα~(d/d)mice die. Besides proliferating epithelial cells, these tumors also contained an expanded population of luteinized stromal cells, which acquire the ability to express P450 aromatase and synthesize E locally. In response to the elevated levels of E, the ERα signaling was accentuated in the ovarian epithelial cells of ERα~(d/d)mice, triggering increased ERα-dependent gene expression, abnormal cell proliferation, and tumorigenesis. Consistent with these findings, treatment of ERα~(d/d)mice with letrozole, an aromatase inhibitor, markedly reduced circulating E and ovarian tumor volume. We have, therefore, developed a unique animal model, which serves as a useful tool for exploring the involvement of E-dependent signaling pathways in ovarian epithelial tumorigenesis. Author Summary Ovarian cancer is currently the most lethal gynecological cancer in the United States. Multiple epidemiological studies indicate that women who take hormone replacement therapy, estrogen or estrogen with progesterone, peri- or postmenopause will have an increased chance of developing ovarian cancer. Unfortunately, the five-year survival rate after diagnosis is very low indicating that better tools are needed to diagnose and treat ovarian cancer. The models that would allow investigation of this disease are severely limited. In this article we introduce a mouse model that develops epithelial ovarian tumors, and by employing inhibitors of estrogen synthesis, we show that ovarian tumorigenesis in this model is dependent on estrogen production within the ovarian tumor. These studies suggest that estrogen may play a role in promoting ovarian tumor growth.