Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

Estrogen and its receptors (ERs) influence many biological processes in physiology and pathology in men and women. ERs are involved in the etiology and/or progression of cancers of the prostate, breast, uterus, ovary, colon, lung, stomach, and malignancies of the immune system. In estrogen-sensitive malignancies, ER beta usually is a tumor suppressor and ER alpha is an oncogene. ER beta regulates genes in several key pathways including tumor suppression (p53, PTEN); metabolism (PI3K); survival (Akt); proliferation pathways (p45(Skp2), cMyc, and cyclin E); cell-cycle arresting factors (p21(WAF1), cyclin-dependent kinase inhibitor 1 (CDKN1A)), p27(Kip1), and cyclin-dependent kinases (CDKs); protection from reactive oxygen species, glutathione peroxidase. Because they are activated by small molecules, ERs are excellent targets for pharmaceuticals. ER alpha antagonists have been used for many years in the treatment of breast cancer and more recently pharmaceutical companies have produced agonists which are very selective for ER alpha or ER beta. ER beta agonists are being considered for preventing progression of cancer, treatment of anxiety and depression, as anti-inflammatory agents and as agents, which prevent or reduce the severity of neurodegenerative diseases.