ER-Alpha36 Mediates Non-Genomic Estrogen and Anti-Estrogen Signaling in Breast Cancer Cells

Estrogen signaling is essential in the initiation and development of neoplasia in mammary gland. In the past several decades, extensive efforts have been dedicated to understand the underlying mechanisms of this important signaling pathway in mammary carcinogenesis, which have facilitated the development of anti-estrogen therapy, the first targeted therapy for human cancer. It has been well documented that the diverse activities of estrogens and anti-estrogens are mediated by specific receptors designated as estrogen receptors (ERs). Currently, there are two identified ERs, ER- and ER-, both of which are ligand-activated transcription factors that stimulate target gene transcription. Compelling evidence indicates that estrogens, especially 17-estradiol (E2), up-regulate the expression and function of c-Myc and cyclin D1, activate cyclin E-Cdk2 complexes and promotes cell cycle progression from G1 to S phase in mammary epithelial cells. Thus, stimulation of target gene expression by ERs in response to estrogens is prevailingly thought to be responsible for estrogen-stimulated mammary carcinoma initiation and progression. Despite the clarity with which ERs have been shown to act as ligand-dependent transcription factors, it became apparent now that not all of the activities mediated by ERs are accomplished through a direct effect on gene transcription. Another signaling pathway (also known as a non-classic, non-genomic, extra-nuclear or membrane-initiated signaling pathway) exists that involves cytoplasmic signaling proteins, growth factor receptors and other membrane-initiated signaling pathways. Several intracellular signaling pathways have been shown cross-talking with the membrane-initiated estrogen signaling: the adenylate cyclase pathway, the phospholipase C pathway, the G-protein-coupled receptor-activated pathways, the PI3K/AKT and the MAPK pathways. Currently, the identity of the membrane-based estrogen receptor that mediates non-genomic estrogen effects has not been fully established. ER-, two forms of ER-, full-length (66-kDa) and short form (46-kDa) have been found on or near the plasma membrane and mediates membrane-initiated estrogen signaling. In addition, there is also evidence indicating that GPR30, an orphan G-protein-coupled-receptor, mediates the rapid, non-genomic responses to estrogens. In 2005, our laboratory identified and cloned a novel variant of ER-, which