One of the fundamental questions in the field of ovarian cancer biology is the cellular origin of serous ovarian cancer. Answering this question will allow us to appropriately design basic and clinical research. The surface epithelium of the ovary is generally accepted as the origin of serous ovarian cancer. However, recent studies have proposed that the fallopian tubes might be another point of origin. This concept is supported by the evidence that early-stage fallopian tube cancers are detected in women with inherited breast cancer genes (BRCA) mutations although the ovaries are normal. These observations suggest that ovarian cancer may originate in the fallopian tubes and spread to the ovaries and abdominal cavity. Simply put, ovarian cancer is the cancer at the ovary, not the cancer of the ovary. This simple change in semantics has profound clinical implications. If ovarian cancer is the cancer at the ovary, it would imply that by the time we see cancer at the ovary, the cancer has already spread beyond its point of origin and become an advanced-stage disease. Therefore, any screening methods designed to detect cancer at the ovary will only find advanced disease. This simple change in semantics, if it is proved to be correct, could change the way we screen for early-stage ovarian cancer. Therefore, results from this study have the potential to translate into clinical practices that involve imaging and molecular screening strategies for ovarian cancer with a focus on changes in the fallopian tubes rather than in the ovaries. This shift in focus to fallopian tubal carcinomas for early-stage cancer detection and screening could also affect how we treat patients with inherited BRCA1 and BRCA1 mutations. Instead of advocating for risk-reducing surgery, these patients may be closely monitored for changes in their fallopian tubes so that surgeries can be delayed beyond child-bearing age without unnecessarily increasing the risk of ovarian cancer. Therefore, advances in understanding the biology of early disease or the spreading of cancer in the late stages are expected to facilitate innovations in early detection of ovarian cancer and treatment for advanced disease. These innovations in turn are expected to reduce the death rate associated with ovarian cancer.

In this proposal, we will generate mouse models with cancer that originated from the fallopian tubes and investigate the involvement of the fallopian tubes in serous ovarian cancer. Using these mouse models, we will characterize early histologic changes in the fallopian epithelium indicative of cancer initiation. Further, we will characterize histologic progression of the tubal cancer and determine whether the progression results in serous ovarian cancer. In addition, using these mouse models, we will investigate the connection between p53 and BRCA1, two genes shown to be important in serous ovarian cancer. Although there are several mouse models of ovarian cancer, those with targeted oncogenesis in the fallopian tubes are lacking. Another important innovation in the research strategy is the application of ovary transplantation to precisely define the process of cancer progression from the fallopian tube to the ovaries. Such experiments would be ethically possible in humans but are required to demonstrate the propensity of tubal cancer to spread as ovarian cancer. Therefore, this proposed study is very important in providing the research community with much needed animal models for tubal cancer. Knowledge gained from these studies will not only enhance our understanding of the cellular origin of cancer, but also contribute to new insights into genetic and histologic changes in early-stage disease and the metastatic progression of serous ovarian cancer.