title: An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations.
abstract: Endometrial 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 β-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.
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, 84132.|Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112.
authors: Chieh-Hsiang
authors: CH
authors: Yang
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, 84132.|Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, 84112.
authors: Aliyah
authors: A
authors: Almomen
authors: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, 84124.
authors: Yin Shen
authors: YS
authors: Wee
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, 84132.|Department of Pathology, University of Utah, Salt Lake City, Utah, 84112.
authors: Elke A
authors: EA
authors: Jarboe
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, 84132.
authors: C Matthew
authors: CM
authors: Peterson
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, 84132.|Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112.|Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, 84112.
authors: Margit M
authors: MM
authors: Janát-Amsbury
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D002869:Chromosome Aberrations; D004195:Disease Models, Animal; D018450:Disease Progression; D065546:Drug Liberation; D004714:Endometrial Hyperplasia / Q000209:etiology* / Q000473:pathology*; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004967:Estrogens / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D004967:Estrogens; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol
keywords: Endometrial cancer; endometrial hyperplasia; estrogen; mouse model