Progesterone Receptor Signaling in the Microenvironment of Endometrial Cancer Influences Its Response to Hormonal Therapy

Abstract

Progesterone, an agonist for the progesterone receptor (PR), can be an efficacious and well-tolerated treatment in endometrial cancer. The clinical use of progesterone is limited due to the lack of biomarkers that predict hormone sensitivity. Despite its efficacy in cancer therapy, mechanisms and site of action for progesterone remain unknown. Using an in vivo endometrial cancer mouse model driven by clinically relevant genetic changes but dichotomous responses to hormonal therapy, we demonstrate that signaling through stromal PR is necessary and sufficient for progesterone anti-tumor effects. Endometrial cancers resulting from epithelial loss of PTEN (PTENKO) were hormone sensitive and had abundant expression of stromal PR. Stromal deletion of PR as a single genetic change in these tumors induced progesterone resistance indicating that paracrine signaling through the stroma is essential for the progesterone therapeutic effects. A hormone refractory endometrial tumor with low levels of stromal PR developed when activation of KRAS was coupled with PTEN-loss (PTENKO/Kras). The innate progesterone resistance in PTENKO/Kras tumors stemmed from methylation of PR in the tumor microenvironment. Add-back of stromal PR expressed from a constitutively active promoter sensitized these tumors to progesterone therapy. Results demonstrate that signaling through stromal PR is sufficient for inducing hormone responsiveness. Our findings suggest that epigenetic de-repression of stromal PR could be a potential therapeutic target for sensitizing hormone refractory endometrial tumors to progesterone therapy. Based on these results, stromal expression of PR may emerge as a reliable biomarker in predicting response to hormonal therapy.

Prediction of Relapse After Therapy Withdrawal in Women with Endometrial Hyperplasia: A Long-term Follow-up Study

“…Our results showed higher levels of glandular PRB and lower stromal PRA levels in the relapsing group compared to non-relapsing women. A recent in vitro study suggested that epigenetic de-repression of stromal PR could be a potential target for sensitizing hormone-refractory endometrial tumors to progesterone therapy and that stromal expression of PR might represent a reliable biomarker in predicting response to hormonal therapy (38). The clinical significance of these findings is not obvious, but continued progestin therapy with long-term use of LNG-IUS might have a therapeutic effect by continuously down-regulating PRB.…”

Epigenetic mechanisms of importance for drug treatment

“…The DNAme status of the Wnt antagonist SFRP5 predicts treatment outcome in cases of non-small-cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors [38]. Similarly, DNAme in the promoter of the progesterone receptor (PR) gene might constitute a biomarker of progesterone sensitivity in endometrial tumors [39].…”

Epigenetic changes as prognostic predictors in endometrial carcinomas

“…The loss of PTEN expression in endometrial cancers causes hormone sensitivity, implying that it may be used as a biomarker for selection of treatment. 8 The identification of additional such candidate genes is an important goal of endometrial cancer research. The aim of the present study was to address the epigenetic differences in a consecutive series of endometrial carcinomas comprising a low-risk group (FIGO-grade 1) and a high-risk group (FIGO-grade 3) with highly significant different treatment outcomes and survival rates.…”