Elevated Estrogen Signaling Drives Tumorigenesis in a Novel Animal Model for Ovarian Epithelial Cancer
Friday, April 6, 2012 • 3:10-3:25 PM
Authors: Mary J. Laws*, Athilakshmi Kannan, Sandeep Pawar, Milan K. Bagchi, and Indrani C. Bagchi
We generated a mouse model where aberrant estrogen receptor alpha (Esr1) signaling in the hypothalamo-pituitary-ovarian axis leads to ovarian tumorigenesis. In this model, termed Esr1d/d, the Esr1 gene is selectively deleted in the anterior pituitary. The Esr1d/d mice form palpable ovarian tumors which display expression of ovarian epithelial tumor markers, cytokeratin 8, WT1 and PAX 8. Besides proliferating epithelial cells, tumors also contain an expanded population of stromal cells. The loss of negative-feedback regulation by estrogen at the level of pituitary led to elevated production of luteinizing hormone, which stimulated ovarian cells to enhance steroidogenesis. Interestingly, stromal cells of the tumor display a high level of P450 aromatase expression, suggesting that these cells acquired the ability to synthesize estrogen. In response to estrogen produced by the stromal cells, the Esr1 signaling is accentuated in the ovarian epithelial cells, triggering abnormal cell proliferation and tumorigenesis. Consistent with this hypothesis, treatment with letrozole, an inhibitor of P450 aromatase, led to a marked reduction in tumor volume when compared to controls. We have, therefore, developed an animal model of ovarian epithelial tumorigenesis, which will serve as a powerful tool for exploring the involvement of estrogen-dependent signaling pathways in the etiology of this cancer.
