title: Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice.
abstract: Cervical cancer is caused by human papillomavirus (HPV) in collaboration with other non-viral factors. The uterine cervix is hormone responsive and female hormones have been implicated in the pathogenesis of the disease. HPV transgenic mice expressing HPV16 oncogenes E6 (K14E6) and/or E7 (K14E7) have been employed to study a mechanism of estrogen and estrogen receptor α (ERα) in cervical carcinogenesis. A chronic exposure to physiological levels of exogenous estrogen leads to cervical cancer in the HPV transgenic mice, which depends on ERα. The receptor is composed of multiple functional domains including a DNA-binding domain (DBD), which mediates its binding to estrogen-responsive elements (EREs) on target genes. A transcriptional control of genes by ERα is mediated by either DBD-dependent (classical) or DBD-independent (non-classical) pathway. Although molecular mechanisms of ERα in cancer have been characterized extensively, studies investigating importance of each pathway for carcinogenesis are scarce. In this study, we employ knock-in mice expressing an ERα DBD mutant (E207A/G208A) that is defective specifically for ERE binding. We demonstrate that the ERα DBD mutant fails to support estrogen-induced epithelial cell proliferation and carcinogenesis in the cervix of K14E7 transgenic mice. We also demonstrate that cervical diseases are absent in K14E7 mice when one ERα DBD mutant allele and one wild-type allele are present. We conclude that the ERα classical pathway is required for cervical carcinogenesis in a mouse model.
authors.affiliation: Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Boulevard, Houston, TX 77204, USA and.
authors.forename: Jieun
authors.initials: J
authors.lastname: Son
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Park
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.forename: Sang-Hyuk
authors.initials: SH
authors.lastname: Chung
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000473:pathology*; D007124:Immunoenzyme Techniques; D051379:Mice; D008822:Mice, Transgenic; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000209:etiology / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16