A Role for Estrogen Receptor alpha36 in Cancer Progression

Estrogen receptor alpha (ER alpha) functions as a ligand dependent transcription factor that directly binds specific estrogen responsive elements, thus regulating the transcription of estrogen sensitive genes. ER alpha has also been shown to be associated with the plasma membrane (membrane associated ER alpha, mER alpha), concentrated in lipid rafts, plasma membrane microdomains with a distinct lipid composition, where it transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein (MAP) kinase signaling pathway. Two isoforms of ER alpha have been described: the traditional ER alpha 66 (66 kDa) and a lower molecular weight variant: the ER alpha 46 (46 kDa). More recently, a novel ER alpha variant with a molecular mass of 36 kDa (ER alpha 36) has been discovered. Notably, ER alpha 36 has been found expressed in different human tumor cells, including both ER- positive and ER- negative breast cancer cells. Estrogen signaling at the cell membrane via ER alpha 36 appears as capable of activating multiple pathways of importance for cancer aggressiveness and metastatic potential. The presence of serum autoantibodies reacting with mER alpha (anti-ER alpha Abs) in a large percentage of patients with breast cancer has recently been reported by our group. These anti-ER alpha Abs seem to act as estrogen agonists rapidly triggering MAP kinase pathway activation thus inducing tumor cell proliferation and overcoming cell resistance to anti-estrogen drug tamoxifen. In this review, we describe the involvement of ER alpha 36 in different tumors. We also report the potential pathogenetic activity of anti-ER alpha Abs and their implication in drug resistance.