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Modulation of Estrogen Response in a Mouse Xenograft Model of Steroid Hormone Sensitive Ovarian Cancer

Women are exposed to estrogen, the female steroid hormone, throughout their reproductive lives. As natural levels of estrogen fall in menopause, some women have taken hormone replacement therapy containing estrogen. When estrogen alone is taken in the menopause, it appears to increase the risk of developing ovarian cancer. 

Estrogen acts through the estrogen receptor (ER). At least 60% of ovarian cancers express the estrogen receptor, but it appears to act differently in ovarian cancers than in breast cancers. My research project is designed to identify estrogen regulated genes in ovarian cancers that may differ from those in breast cancers. We are also investigating drugs that inhibit estrogen receptor action in breast cancer, such as tamoxifen and letrozole in ovarian cancers.

Extended use of estrogen is difficult to mimic in short term cell culture models. For this reason, I have developed a unique ovarian cancer mouse model which allows rigorous, long-term, control of the steroid hormone (estrogen) microenvironment. When ER⁺ ovarian cancer cells are introduced into the model, they grow significantly. ER^- cells in the same model demonstrate some growth, but lag behind the ER⁺ cells.

Women with advanced ovarian cancer are initially treated with a combination of surgery, followed by chemotherapy. Several maintenance chemotherapies have been tried to decrease the risk of recurrence; however, antiestrogen or aromatase inhibitor therapy has not been tried in this setting as a secondary preventative agent. We will use the mouse model to test the antiestrogen tamoxifen and aromatase inhibitor letrozole for effectiveness in inhibiting growth of ovarian tumors. In addition, we will examine ovarian tumors treated with estrogen, tamoxifen and letrozole to identify different patterns of gene expression.

Development of the mouse model has placed my research in a unique position to define the role of estrogen in the development and recurrence of ovarian cancer. The goal of this project is to identify new drug targets from the sets of estrogen regulated genes identified in our model system. In addition, our research may define a subset of women with ovarian cancer who may benefit from the addition of a hormonal agent to the standard chemotherapy.