Grant: Project Grant

For most women, the largest risk factor for ovarian cancer is the monthly ovulation. Oral contraceptives prevent ovulation and can reduce ovarian cancer risk by up to 35%, but how ovulation increases risk is not clear. In trying to find an explanation, our lab has found that ovaries from aged mice and post-menopausal women, which have had many ovulations, harbor a population of cells that are known to suppress the activity of the immune system. These cells were not found in young ovaries. We predict that these cells play a critical role in allowing both primary and metastatic cancers to grow in the ovary. The accumulation of immune suppressing cells in the aging ovary is associated with fibrosis. We have created a mouse model that develops ovarian fibrosis and the question we are asking is: Can this process be blocked or reversed? Metformin, a drug used mostly by diabetes patients, has been shown to reduce fibrosis in other tissues, and diabetic women who take metformin have a dramatic decrease in the incidence of ovarian cancer. We therefore propose to determine the contribution of fibrosis to the recruitment of immunosuppressive cells to the ovary, determine how the development of fibrosis is accelerated in women with BRCA mutations, and explore how metformin can prevent or reverse these changes. Our results would open the door to the possibility that metformin could be used for ovarian cancer prevention in women at high risk.