Estrogen receptors alfa (ERα) and beta (ERβ) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11

The mitogenic effect of 17 beta-estradiol (E2) on the breast is mediated by estrogen receptor alfa (ER alpha), hence ER alpha antagonists are effective in the treatment of breast cancer. The possible use of estrogen receptor beta (ER beta) as a target in treatment of breast cancer is under investigation. The mouse mammary cell line HC11 expresses both ERs and was used to study the role of the two receptors in proliferation. E2 had no effect on proliferation. The ER alpha-selective agonist 4,4',4''-(4- propyl-(1H)- pyrazole- 1,3,5-triyl) trisphenol (PPT) stimulated proliferation. The ER beta-selective agonist 2,3-bis(4-hydroxy-phenyl)- propionitrile (DPN) inhibited cell growth and induced apoptosis. PPT upregulated while DPN downregulated cyclin D1 and proliferating cell nuclear antigen (PCNA). Upon inhibition of ER alpha expression with RNA interference, E2 caused a decrease in cyclin D1 and PCNA, and increased apoptosis. When ER beta expression was blocked, E2 induced proliferation and cells gained the capacity to grow in soft agar. In summary, in HC11 mammary epithelial cells, ER alpha drives proliferation in response to E2 while ER beta is growth inhibitory. The lack of effect of E2 on HC11 cell growth is the result of the combined actions of ER alpha (proliferation) and ER beta (apoptosis). We suggest that use of ER beta agonists will be a useful addition in treatment of breast cancer, which, at present, is only aimed at inhibition of ER alpha.