Membrane progesterone receptors β and γ have potential as prognostic biomarkers of endometrial cancer

Endometrial cancer (EC) is one of the most common malignancies in women worldwide. EC is linked to chronic exposure to estrogens that is unopposed by protective effects of progesterone. Progesterone modulates gene expression via classical nuclear receptors, and has rapid effects via the less characterized membrane-bound progesterone receptors (mPRs) of the progestin and adipoQ receptor (PAQR) family. The presence of mPRs in EC has not been investigated to date. The aims of this study were to examine PAQR7, PAQR8 and PAQR5, which encode for mPR alpha, mPR beta and mPR gamma, respectively, for their expression and localization in EC tissue and adjacent control endometrium. Our results reveal decreased expression of PAQR7 and PAQR8, and unaltered expression of PAQR5 in EC versus control tissue. Expression of PAQR5 was decreased in EC with higher FIGO stage versus stage IA. Immunohistochemistry revealed lower levels of mPRa and mPR beta, but higher levels of mPR gamma, in EC versus control tissue. There was greater decrease in mPR beta levels in tumors with lymphovascular invasion. The analysis of the expression data associates higher PAQR5 mRNA and mPR beta protein levels with favorable patient prognosis. Immunohistochemistry showed diverse localizations of mPRs in control and cancer endometrium. In control endometrium, mPRa and mPR beta were localized mostly at the cell membranes, while mPR gamma was localized in the cytoplasm and/or nucleus. In cancer endometrium, mPRa and mPR beta were detected at the cell membrane or in the cytoplasm, or both, while mPR gamma was only localized in the cytoplasm. Taken together, these results imply that mPRs are involved in EC pathogenesis through effects on the development or progression of cancer. The potential role of mPR beta and mPR gamma as prognostic biomarkers needs to be further assessed on a larger number of samples.