Prevention and effective treatment of cancer require a deep understanding of the pathogenesis of a malignancy. As ovarian cancer is mostly diagnosed in advanced stages, however, the mechanisms underlying its etiology, inception, and progression remain poorly understood. Our proposed research aims to define progesterone signaling as a vital early intrinsic factor determining ovarian cancer development, particularly for high-risk women carrying a pathogenic BRCA1 or 2 mutation. High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest ovarian cancer type. One approach to overcome the present knowledge gap in ovarian cancer pathogenesis would be to use an animal model faithfully reproducing the clinical disease with molecular similarity to the human cancer. To this end, we developed mouse models that recapitulate the clinical metastases of human HGSC with histological, molecular, and genomic similarities. Applying one of these mouse models of HGSC, we have demonstrated that the ovarian hormone progesterone is a pivotal intrinsic factor inducing the development of HGSC equipped with metastatic capability. Crucially, mifepristone, an FDA-approved inhibitor of progesterone signaling, markedly extended survival of these mice by blocking the development and metastases of HGSC. Accordingly, these preclinical findings point to a compelling concept that progesterone signaling is a potential prophylactic target for ovarian cancer prevention, particularly for high-risk women, such as BRCA1/2-mutation carriers. In the proposed research, we will examine this progesterone hypothesis by interrogating the vital early role and mechanism of progesterone signaling in the development and metastasis of HGSC using a Brca1 model; and by examining genomic and metabolomic abnormalities influencing steroid hormone synthesis and response in BRCA1/2-mutation carriers.