title: Infiltrating Macrophages Induce ERα Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen.
abstract: Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68(+)CD163(+) macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68(+)CD163(+) macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting.
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Ning
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China. Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors.forename: Bingying
authors.initials: B
authors.lastname: Xie
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shan
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China.
authors.forename: Bingyi
authors.initials: B
authors.lastname: Yang
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China.
authors.forename: Xuezhen
authors.initials: X
authors.lastname: Luo
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of pathology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, P.R. China.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: He
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Jin
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China. xiaojunchen2013@sina.com zhangzhenbozzb@aliyun.com.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China. xiaojunchen2013@sina.com zhangzhenbozzb@aliyun.com.
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors.forename: Youji
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D011379:Prognosis; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C508717:IL17A protein, human; D020381:Interleukin-17; D004958:Estradiol