Investigating the Balance Between Estrogen Receptor Mediated Cell Proliferation and Genomic Surveillance

Breast cancer is a leading cause of cancer in women and the second leading cause of cancer death. Lifetime exposure to estrogen contributes to this risk but high dose estrogen has been used to induce apoptosis as treatment for breast cancer. These opposing tumorigenic and anti-tumorigenic effects of estrogen may be regulated differently by the two Estrogen Receptors (ER), Estrogen Receptor alpha (ERα) and Estrogen Receptor beta (ERβ). Although the receptors share a 96% homology in their DNA binding domain, they are unique in the ligand-binding domain with 53% amino acid homology. Previous studies have shown that ERα drives cell proliferation in the mammary gland. We propose that ERβ mediates genomic surveillance in the mammary gland to restrict proliferation. To test this hypothesis we first characterized each of our reference breast cancer cell lines to determine the ERα and ERβstatus. We found that ERβ transcript and protein are expressed in some breast cancer cell lines that are considered to be “triple-negative” (HCC1937 and MDA MB 231). Using specific ER agonists, we were able to demonstrate that amphiregulin, a secreted protein and a marker of ERα activation, is upregulated by ERα agonists in a dose dependent manner in cell lines that have ERα (T47D & MCF7). ERα agonists do not enhance AREG expression in cell lines that primarily expresses ERβ (HCC1937). Instead, CEBPd, a tumor suppressor, is expressed at high levels in this cell line. In conclusion, targeting ERβ has the potential to selectively activate tumor suppressor pathways without stimulating proliferation and may provide a treatment option for patients for whom inhibition of ERa is not an option