Abstract 64: A p53 activating mutation drives metastatic high-grade serous ovarian cancer arising from the ovary in mice

Abstract

Abstract The tumor suppressor p53 is the most frequently mutated gene in high-grade serous ovarian cancer, or high-grade serous carcinoma (HGSC) − the most common and deadliest ovarian cancer. Yet it remains unknown whether p53 mutation can drive HGSC. To address this, we have incorporated a p53 activating mutation, p53R172H, into conditional Dicer-Pten double-knockout (DKO) mice, generating triple-mutant (TKO) mice. Like DKO mice, these TKO mice develop fallopian-tube-originated HGSCs, aggressively metastasizing inside the abdominal cavity, inducing ascites, and killing the mice. Then, unlike DKO mice, when both fallopian tubes are surgically removed from TKO mice, TKO ovaries alone are capable of developing HGSCs, which also metastasize to the abdominal cavity, including the omentum, diaphragm, and mesentery. This finding indicates that p53 mutation can drive HGSC in the ovary. To further examine the ability of p53 mutation to drive ovarian HGSC, we have generated p53R172H-Pten double-mutant mice (DMu), a control line for TKO mice. Intriguingly, 30% of the DMu mice (12/40 mice) develop metastatic HGSCs in the ovary, which spread to the abdominal cavity before killing the mice, just like TKO mice with fallopian tubes removed. Unlike TKO and DKO mice, however, DMu mice show no sign of tumor in the fallopian tube. Our new mouse models of ovarian cancer therefore show that p53 mutation indeed can initiate and drive metastatic HGSCs arising from the ovary. Clinically, our study suggests that besides the fallopian tube, the ovary can serve as a source of high-grade serous ovarian cancer. (Grant support: Ovarian Cancer Research Fund (OCRF); Marsha Rivkin Ovarian Cancer Challenge Grant; F32 NCI National Research Service Award (NRSA); K99/R00 NCI Pathway to Independence Award) Citation Format: Jaeyeon Kim, Donna M. Coffey, Lang Ma, Martin M. Matzuk. A p53 activating mutation drives metastatic high-grade serous ovarian cancer arising from the ovary in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 64. doi:10.1158/1538-7445.AM2014-64