Abstract DPOC-007: PROGESTERONE/PR ERADICATES p53–DEFECTIVE CELLS IN THE FALLOPIAN TUBE EPITHELIUM BY INDUCTION OF NECROPTOSIS

Abstract

Abstract Cervical Cancer Prevention Center, Department of Research, Tzu Chi Medical Center, Hualien, Taiwan, Republic of China. Institute of Medical Sciences, Tzu Chi University, Taiwan, Republic of China. The fallopian tube (FT) fimbriae, which are regularly exposed to ovulatory carcinogens, have been identified as the origin of high–grade serous ovarian carcinoma (HGSOC), with loss of p53 determined to be a universal and the earliest step of carcinogenesis. In previous studies, we have identified ROS in ovarian follicle is highly mutagenic and toxic to the fallopian tube fimbria that bath in the ovulatory follicular fluid (FF) after ovulation. We also found that loss of p53 renders fimbrial epithelial cells less vulnerable to the ROS stress, and that hemoglobin in ovulated FF could rescue the ROS–stressed fimbrial epithelial cells from apoptosis. Given that both ovulation and retrograde menstruation, the two proven risk factors for HGSOC, are commonplace in menstrual cycles, and that occurrence of tubal p53 signature is frequent but HGSOC is rare, we hypothesize that luteal–phase progesterone (P4) is responsible for clearance of p53–defective epithelial lesions as a natural protection. Herein, we show that P4 and progesterone receptor (PR) induce necroptosis of tubal epithelial cells in p53–null mice and in immortalized p53–deficient human fimbria epithelial cells through the TNF–α/RIPK1/RIPK3/p–MLKL pathway. The clearance acts regularly in the luteal phase of the menstrual cycle, recovering shortly thereafter, and can be augmented with P4 supplementation. With the inhibition of PR, the oviduct epithelium of Trp53–null mice escapes the clearance and, upon repeated ovulation exposures, accumulates DNA double–strand breaks. Through the induction of necroptosis of p53–deficient epithelial cells, luteal phase P4 prevents the transformation of the FT epithelium after ovulation. This protection can be augmented with P4 supplementation. Citation Format: Tang–Yuan Chu, MD, PhD. PROGESTERONE/PR ERADICATES p53–DEFECTIVE CELLS IN THE FALLOPIAN TUBE EPITHELIUM BY INDUCTION OF NECROPTOSIS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-007.