Abstract 328: A p53 activating mutation accelerates the progression of high-grade serous ovarian cancer arising from the fallopian tube.

Abstract

Abstract The tumor suppressor p53 is the most frequently mutated gene in high-grade serous ovarian cancer, the deadliest subtype responsible for 70% of all ovarian cancer deaths. Yet the precise role of p53 mutation in ovarian cancer remains unknown. To address this, we have incorporated a p53 activating mutation, p53R172H, into conditional Dicer-Pten double-knockout (DKO) mice, which develop metastatic high-grade serous carcinomas originating in the fallopian tube, to generate triple-mutant (TKO) mice (p53 LSL-R172H/+ Dicer flox/flox Pten flox/flox Amhr2 cre/+). Like DKO mice, these TKO mice develop high-grade serous carcinomas aggressively metastasizing throughout the abdominal cavity, inducing ascites and causing death. These TKO mice, however, die significantly earlier than DKO mice (average survival: 7.3 (n=31) for the TKO mice vs. 9.4 (n=24) months for the DKO mice; p<0.0001). Despite the overall similar extent of tumor burden and metastasis, TKO tumors appear to spread faster than DKO tumors. In TKO mice, tumor cells originating in the fallopian tube acutely penetrate the ovary, as marked by fallopian tube-specific epithelial markers, cytokeratin 14 and 17. In contrast, the ovary of DKO mice remains intact, largely free of metastasis during tumor progression. Moreover, unlike DKO ovaries, which alone fail to develop any tumors, TKO ovaries are able to initiate and develop metastatic ovarian tumors even after the fallopian tubes are removed, suggesting a tumor-initiating role of p53 mutation in the ovary. Collectively, these results thus reveal the critical role of p53 mutation in initiation and progression of ovarian cancer (Grant support: Ovarian Cancer Research Fund (OCRF); F32 National Research Service Award (NRSA)). Citation Format: Jaeyeon Kim, Donna M. Coffey, Lang Ma, Martin M. Matzuk. A p53 activating mutation accelerates the progression of high-grade serous ovarian cancer arising from the fallopian tube. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 328. doi:10.1158/1538-7445.AM2013-328