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

Abstract

The mitogenic effect of 17beta-estradiol (E2) on the breast is mediated by estrogen receptor alfa (ERalpha), hence ERalpha antagonists are effective in the treatment of breast cancer. The possible use of estrogen receptor beta (ERbeta) 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 ERalpha-selective agonist 4,4',4''-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) stimulated proliferation. The ERbeta-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 ERalpha expression with RNA interference, E2 caused a decrease in cyclin D1 and PCNA, and increased apoptosis. When ERbeta expression was blocked, E2 induced proliferation and cells gained the capacity to grow in soft agar. In summary, in HC11 mammary epithelial cells, ERalpha drives proliferation in response to E2 while ERbeta is growth inhibitory. The lack of effect of E2 on HC11 cell growth is the result of the combined actions of ERalpha (proliferation) and ERbeta (apoptosis). We suggest that use of ERbeta agonists will be a useful addition in treatment of breast cancer, which, at present, is only aimed at inhibition of ERalpha.