Overexpression of progesterone receptor A isoform in mice leads to endometrial hyperproliferation, hyperplasia and atypia

Abstract

A delicate balance in estrogen and progesterone signaling through their cognate receptors is characteristic for the physiologic state of the endometrium, and a shift in receptor isotype expression can be frequently found in human endometrial pathology. In this study, using a transgenic mouse model, we examined the mechanisms whereby alterations in progesterone receptor (PR) isotype expression leads to endometrial pathology. For an experimental model, we used transgenic mice (PR-A transgenics) carrying an imbalance in the native ratio of the two PR isoforms A and B (PR-A and PR-B) through the expression of additional A form and examined their uterine phenotype under different hormonal regimens, using various criteria. Uterine epithelial cell proliferation was augmented in PR-A transgenics and was abolished by PR antagonists. In particular, proliferative response to progesterone, independent of signaling through estrogen, was enhanced. Upon continuous exposure to estradiol and progesterone, the uteri in PR-A transgenics displayed gross enlargement, endometrial hyperplasia including atypical lesions, endometritis and pelvic inflammatory disease. Imbalanced expression of the two isoforms of PR in a transgenic model reveals multiple derangements in the regulation of uterine physiology, resulting in various pathologies including hyperplasias.

Progesterone action in breast, uterine, and ovarian cancers

“…This delicate balance of PR isoforms is further illustrated with transgenic mice overexpressing PR-A in glandular epithelium and stromal tissue. This experimental increase in the PR-A:PR-B ratio results in endometrial hyperplasia and atypia with enhanced expression of uterine epithelial growth factors such as amphiregulin known to be regulated by progesterone; these effects can be abolished by treatment with the anti-progestin, mifepristone (Fleisch, et al 2009). These results show that progesterone can be either an anti- or pro-proliferative force on the endometrium depending on isoform expression.…”

Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyosis

“…Fertil Steril 2011. related to reduced expression of progesterone-dependent genes, especially in the secretory phase of the menstrual cycle (55). The physiologic effects of progesterone in the uterus are varied (33), but some recent studies have suggested that the development of uterine abnormalities, such as adenomyosis and cancer, might arise from a ''misregulation in the relative expression of the two main PR isoforms'' rather than PR expression being a marker of disease (56). Our data in the human suggest this might be the case because PR-A/ PR-B ratios remained similar to those of the normal uterus, albeit with consistently lower PR-A and PR-B expression in adenomyosis.…”

Progesterone receptor A mediates VIP inhibition of contraction

“…P4 activates two subnuclear receptors or transcription factors, raising the possibility that each of these two P4 actions may be mediated by a different P4 receptor. This hypothesis is supported by several studies performed in a variety of normal and dysplastic cells showing that P4 receptor A (PR-A) and PR-B have different functions (8,16,23,32). We have shown that PR-B is responsible for downregulating Gq/11 because P4 receptor transfection of normal colon muscle cells increases their sensitivity to P4-reduced Gq/11 protein expression and impaired contraction (8).…”

“…P4, VIP, 8=bromo-c=AMP (8B-c=AMP), (16), and G protein subunit antibodies were purchased from CytoSignal (Irvine, CA), and antibodies against PR-A and PR-B were from Cayman Chemical (Ann Arbor, MI) (13).…”