Ovarian cancer is a devastating disease that affects 22,000 women yearly in the United States. Serous ovarian cancer, which constitutes about 70% of all epithelial ovarian cancer, is the deadliest. Understanding differentiation of ovarian cancer histotypes provides the possibility of subtype-specific treatment for this deadly disease. Tumor suppressor genes upstream of mTORC1, STK11, PTEN, and TSC2, are deleted in 88%, 40%, and 55% of high grade serous ovarian cancer, respectively. In deleting these genes alone and in combinations in the ovarian surface epithelium of mice, we found that papillary serous ovarian cancer histology only developed with deletion of Stk11 and Pten. These tumors are positive for high grade serous ovarian cancer markers including PAX8 in most 15-20 week old ovaries indicating that PAX8 1) is not an early driver of differentiation and 2) is acquired during transformation of ovarian surface epithelial cells. When isolated and cultured, these cells have higher growth rates in vitro than single mutants or controls. RNA sequencing of control, Stk11cko, Ptencko, and Stk11ckoPtencko mouse ovarian surface epithelial cells reveals that Stk11ckoPtencko cluster away from other groups and have over 3000 differentially expressed genes versus control. Interestingly, Pten transcripts are twice as abundant in Stk11cko versus control revealing a compensatory mechanism inhibiting uncontrolled growth. Gene set enrichment analysis of Stk11ckoPtencko versus Stk11cko indicates many DNA repair pathways are dysregulated. Together, these results highlight the important roles that Pten and Stk11 deletion play in papillary serous ovarian cancer and provide evidence to further investigate therapies that target these pathways.
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