Roles of estrogen receptor α and β in the regulation of proliferation in endometrial carcinoma.

Endometrial carcinoma (EC), an estrogen-dependent gynecological malignancy, is prevalent worldwide. Estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) are two main estrogen receptor isoforms, which mediate estrogen-induced proliferation in EC. However, the dynamic changes of ER alpha and ER beta subtype expression and their functions on proliferation in EC remain elusive. In this study, we aimed to investigate the expression of ER alpha and ER beta in para-tumor eutopic endometrium, endometrial atypical hyperplasia and EC by immunohistochemistry and then analyse their clinical significance. Subsequently, Ishikawa cells with ER alpha or ER beta knockdown by lentivirus transfection were used to explore the relationship between ER alpha/ER beta and cell proliferation, and preliminarily evaluate whether metformin's inhibitory effect on estrogen-induced cell proliferation was mediated by ER alpha and ER beta. We found that the expression of ER alpha and ER beta were markedly changed in endometrial hyperplasia and EC compared with that in para-tumor eutopic endometrium and exhibited different expression trends. Through further analysis, we discovered that ER alpha presented higher expression in endometrial atypical hyperplasia and early stage of EC than that in para-tumor eutopic endometrium, while the expression of ER beta gradually decreased from para-tumor eutopic endometrium to EC. Additionally, the cell cyclerelated protein, CyclinD1 was gradually increased but p21 decreased. Furthermore, knockdown of ER alpha and ER beta severally in Ishikawa cells either inhibited or promoted estrogen-induced cell proliferation through regulating CyclinD1 and p21 expression. Meanwhile, the inhibitory effect of metformin on estrogen-induced cell proliferation was respectively blunted or partly reversed by knockdown of ER alpha or ER beta. Altogether, ER alpha and ER beta have different expression patterns in the progression of EC either facilitating or suppressing cell proliferation through regulating the expression of CyclinD1 and p21 in EC cells, and may also mediate the inhibitory effect of metformin on estrogen-induced EC cells proliferation.