Research ArticleCancer

Constitutive expression of progesterone receptor isoforms promotes the development of hormone-dependent ovarian neoplasms

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Science Signaling  06 Oct 2020:
Vol. 13, Issue 652, eaaz9646
DOI: 10.1126/scisignal.aaz9646

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Progesterone receptor imbalance causes ovarian cancer

Changes in the relative abundance of the progesterone receptor isoforms PGRA and PGRB are associated with female reproductive tract cancers. Wetendorf et al. engineered mice to overexpress PGRA or PGRB in PGR-producing tissues. Whereas a small number of mice overexpressing PGRA developed ovarian tumors, all mice overexpressing PGRB developed tumors. The tumors shared a gene expression signature with human ovarian and endometrial cancers and exhibited increased expression of genes that promote cell cycling, including Ccnd1, which was a direct target of PGRB. The PGR antagonist RU486 reduced tumor growth and the expression of cell cycle–related genes in PGRB-overexpressing mice. These findings identify PGR isoform–specific effects on cellular proliferation and may explain why an imbalance in the isoform ratio is associated with reproductive tract cancers in women.

Abstract

Differences in the relative abundances of the progesterone receptor (PGR) isoforms PGRA and PGRB are often observed in women with reproductive tract cancers. To assess the importance of the PGR isoform ratio in the maintenance of the reproductive tract, we generated mice that overexpress PGRA or PGRB in all PGR-positive tissues. Whereas few PGRA-overexpressing mice developed reproductive tract tumors, all PGRB-overexpressing mice developed ovarian neoplasms that were derived from ovarian luteal cells. Transcriptomic analyses of the ovarian tumors from PGRB-overexpressing mice revealed enhanced AKT signaling and a gene expression signature similar to those of human ovarian and endometrial cancers. Treating PGRB-overexpressing mice with the PGR antagonist RU486 stalled tumor growth and decreased the expression of cell cycle–associated genes, indicating that tumor growth and cell proliferation were hormone dependent in addition to being isoform dependent. Analysis of the PGRB cistrome identified binding events at genes encoding proteins that are critical regulators of mitotic phase entry. This work suggests a mechanism whereby an increase in the abundance of PGRB relative to that of PGRA drives neoplasia in vivo by stimulating cell cycling.

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