An estrogen‐induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations

Abstract

a These authors contributed equally to this study. AbstractEndometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in b-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH.

DNA methylation promotes paired box 2 expression via myeloid zinc finger 1 in endometrial cancer

“…In gynecological diseases, PAX2 is hypomethylated in tamoxifen-induced endometrial cancer [19]. We also performed bisulfite sequencing on the same region in this paper but revealed hypermethylation in endometrial cells (data not shown).…”

Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor α In Endometrial Cancer

“…We used an estrogen-induced endometrial hyperplasia model that uses a slow-release E2 pellet (Yang et al, 2015). We found that 3 weeks of Dex treatment, in the absence of excess E2, reduced uterine weight by 21% (p = 0.042, t test), whereas 10 weeks of E2 exposure increased uterine weight by 52% (p = 0.002, t test) (Figures 2B and 2C).…”

“…To induce estrogen-driven endometrial hyperplasia, E2 pellets were prepared and surgically implanted into mice (n = 21), as previously described (Yang et al, 2015). Following 10 weeks of E2 exposure, mice were divided into three treatment arms to receive Dex, PBS, and 5% ethanol (n = 7 per arm).…”

“…Of endometrial cancers, 80%–90% are type I endometrioid tumors that express ER and are thought to be hormonally driven (Saso et al, 2011). Estrogen causes increased uterine growth and continued exposure can lead to endometrial hyperplasia (Yang et al, 2015). In contrast to the pro-growth role of ER in the uterus, GR reduces uterine growth and opposes phenotypic effects of estrogens in the uterus (Bever et al, 1956; Bitman and Cecil, 1967).…”

What maintains the high intra-follicular estradiol concentration in pre-ovulatory follicles?

“…It is a potent hormone in comparison to other steroids, exerting its action in a concentration several orders of magnitude lower. Disruption of the control of estradiol serum concentration may cause infertility, thrombosis, and even cancer [28]. Only the unbound fraction of estradiol, about 2 %, is bioactive while the rest of the estradiol in serum is bound to proteins, predominantly SHBG and albumin.…”