Loss of Induces Granulosa Cell Defects and Development of Ovarian Tumors in the Mouse.

Genetic alterations of the gene are associated with a variety of malignancies, including female-related cancers. The role of as either a tumor suppressor gene or an oncogene is tissue-dependent and varies based on the cancer type. Both the amplification and deletion of the gene have been associated with ovarian cancer in humans. In this study, we investigated the effects of loss on ovarian pathogenesis in mice. A conditional loss of in the somatic cells of the ovary led to an increased prevalence of ovarian tumors in aged mice. By the age of 15 months, 27% of knockout (KO) females developed ovarian tumors that presented characteristics of granulosa cell tumors. While ovaries from young adult mice did not display tumors, they all contained abnormal follicle-like lesions. The granulosa cells composing these follicle-like lesions were quiescent, displayed defects in differentiation and were organized in a rosette-like pattern. The RNA-sequencing analysis further revealed differentially expressed genes in KO ovaries, including genes involved in metaplasia, ovarian cancer, epithelial cell development, tight junctions, cell-cell adhesion, and the Wnt/beta-catenin pathway. Together, this study showed that is required for normal granulosa cell differentiation and prevention of ovarian tumor development in mice.