Epithelial ERα Is Dispensable for the Development of Estrogen-Induced Cervical Neoplastic Diseases.

Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E-2) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E-2 mainly functions through oestrogen receptor alpha (ER alpha). However, the role of ER alpha in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ER alpha-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not in the stroma. We found that E-2 induced cervical epithelial cell proliferation in epithelial ER alpha-deficient mice. We also found that E-2 promoted the development of CIN and CxCa in epithelial ER alpha-deficient K14E7 mice and that all neoplastic epithelial cells were negative for ER alpha. In addition, proliferation indices were similar between ER alpha(-) and ER alpha(+) CxCa. These results indicate that epithelial ER alpha is not necessary for E-2-induced CIN and CxCa. Taking these findings together, we conclude that stromal ER alpha rather than epithelial ER alpha mediates oncogenic E-2 signalling in CxCa. Our results support stromal ER alpha signalling as a therapeutic target for the disease. Copyright (C) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.