A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Postmenopausal women on estrogen replacement therapy (ERT) have a reduced risk of developing colon cancer compared with postmenopausal women not on ERT, suggesting a role for estradiol (E-2) in protection against this disease. To determine whether E-2 protects against inflammation-associated colon cancer when administered following the initiation of colonic DNA damage, in this study, we implanted E-2-containing pellets into mice after co-treatment with azoxymethane and two rounds of dextran sulfate sodium (DSS). Wild-type (WT) E-2-treated mice had reduced numbers and average area of adenocarcinomas compared with the control mice. These effects were lost in estrogen receptor-beta (Er beta (Esr2)) knockout mice. Surprisingly, apoptosis was reduced and cell proliferation was increased in sections from tumors of the WT E-2 mice compared with the WT control mice. These findings are probably due, in part, to a reduction in ER beta expression in colonic epithelial cells as the cells progressed from a non-malignant to a cancerous state as enhanced apoptosis was observed in normal colonocytes expressing higher levels of ER beta. Furthermore, epithelial cells within the tumors had dramatically increased ER alpha mRNA and protein expression compared with the non-diseased mice. We conclude that while E-2 treatment resulted in an overall suppression of colonic adenocarcinoma formation, reduced ER beta expression accompanied by enhanced ER alpha expression caused an altered colonocyte response to E-2 treatment compared with the earlier stages of colon cancer development. These data are the first examples of decreased ER beta expression concurrent with increased ER alpha expression as a disease develops and highlight the importance of understanding the timing of E-2 exposure with regard to the prevention of inflammation-associated colon cancer.