Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Na-Yiyuan Wu, Hsuan-Shun Huang, Tung Hui Chao, Hsien Ming Chou, Chao Fang, Chong-Zhen Qin, Chueh-Yu Lin, Tang-Yuan Chu, Hong Hao Zhou
High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53^−/− mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.

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Teaser

Ovarian high-grade serous carcinomas (HGSOC) originate mainly from the fallopian tube epithelium and exclusively carry early TP53 mutations. Wu et al. find that progesterone, acting via its receptor, induces necroptosis of p53-deficient tubal epithelial cells. Supplementation of progesterone in diestrus further augments this clearance, suggesting that progesterone may be chemopreventive for HGSOC.


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