Ovulation, inclusion cysts, and p53 mutations in a mouse model of ovarian cancer

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DESCRIPTION (provided by applicant): Ovarian cancer is the most lethal gynecological malignancy among western women. The etiology of ovarian cancer is unknown, but intervention that blocks ovulation reduces the risk for developing ovarian cancer. For example, pregnancy, breast-feeding, use of oral contraceptives, and early menopause all reduce the risk for developing ovarian cancers. Ovarian inclusions cysts are possible precursor lesions of ovarian cancer. Alternatively, ovarian cancers may arise in fallopian tubal epithelial cells. We have developed a Smad2 dominant negative (Smad2DN) mouse that develops epithelial-lined ovarian inclusions cysts that resemble the fallopian epithelium (endosalpingiosis). When these animals are chronically superovulated for six months, they develop significantly more ovarian inclusions cysts than their normal littermate counterparts that are ovulation suppressed, but these cysts never developed into cancer. We hypothesize that the transition of ovarian inclusion cysts to cancer is a two hit process. In at least three other models of ovarian cancer, the mutation of p53 is required for lesions to develop. We therefore propose to develop a Smad2DN/floxedp53 bitransgenic mouse to provide the first animal model to directly investigate the link between ovulation and the transition of ovarian inclusion cysts or tubal epithelial cells into cancers. Specific Aim 1 will investigate the presence of ovarian cancer at 6 and 12 months in Smad2DN mice with the floxed p53 allele deleted in the ovarian surface using cre-recombinase intrabursal injections. Specific Aim 2 will investigate ovarian cancer in Smad2DN/floxedp53 mice with the floxed p53 allele deleted in the tubal epithelium using cre-recombinase intratubal injections. Specific Aim 3 will then compare superovulated and ovulation suppressed Smad2DN/floxedp53 mice with p53 deleted in either the OSE or the tube to investigate increased formation of cancers in response to ovulation in animals that have both the Smad and p53 pathways inactivated. Development of this model will provide two pathways for further investigation critical in ovarian cancer, p53 and Smad signaling. The model will help explore if inactivation in the tube or the ovary contributes to serous cancers. Lastly, will be able to conduct future studies in this mouse model aimed at generating therapies that prevent ovarian cancer.