Abstract
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.
Highlights
Epithelial ovarian cancer (EOC) is one of the most devastating cancers prevalent in women worldwide
Through Progesterone Receptors, P4 Induces Cytolysis and Cell Flaking in the Oviduct Epithelium of Trp53À/À Mice during Diestrus To investigate the effect of P4 on fimbrial epithelial cells in the menstrual cycle, Trp53À/À or wild-type mice were superovulated with or without P4 supplementation and progesterone receptor (PR) inhibition using mifepristone (RU486; Figure 1A)
These changes were exacerbated when P4 was supplemented at diestrus (Figure 1B, Trp53À/À/P4/Diestrus) but completely disappeared when the PR inhibitor RU486 was administered before the P4 supplement (Figure 1B, Trp53À/À/P4+RU/Diestrus)
Summary
Epithelial ovarian cancer (EOC) is one of the most devastating cancers prevalent in women worldwide. High-grade serous ovarian cancer (HGSOC) accounts for the majority of EOCs and the related deaths (Siegel et al, 2013). The clinical outcomes of HGSOC have not changed significantly over the past three decades, mainly because of a lack of knowledge about its etiology and natural history. Given the lack of an effective means for the early detection of EOC, generating effective prevention options is vital. Loss of p53 functioning seems to be a necessary and early event in the malignant transformation of tubal epithelium, with the TP53 mutation being identified in virtually all HGSOCs (Ahmed et al, 2010) and in the tubal precursor of serous tubal intraepithelial carcinomas (STICs) (Kuhn et al, 2012)
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