Role of Receptor Complexes in the Extranuclear Actions of Estrogen Receptor Alpha in Breast Cancer

Our recent studies have examined the role of various receptor complexes in the mediation of rapid, extranuclear effects of estradiol. This review describes 17beta-estradiol (E2)-initiated extranuclear signaling pathways, which involve the insulin-like growth factor 1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) and result in the activation of several kinase cascades. The biologic results of these effects are the enhancement of cell proliferation and diminution of programmed cell death (apoptosis). Until recently, most studies assigned priority to the nuclear transcriptional actions of estrogen receptor alpha (ER alpha). Present investigative emphasis focuses on the additional importance of ER alpha residing in or near the plasma membrane. A small fraction of ER alpha is associated with the cell membrane and mediates the rapid effects of E2. Unlike classical growth factor receptors, such as IGF-1R and EGFR, ER alpha has no transmembrane and kinase domains and is known to initiate E2 rapid signals by forming protein/protein complexes with many signaling molecules. Our recent studies demonstrate that the IGF-1R is involved in tethering ER alpha to the plasma membrane, in activating the EGFR, and in the initiation of mitogen-activated protein kinase and phosphoinositide 3-kinase signaling. The formation of a multi-protein complex containing these receptors as well as adaptor proteins is a critical step in this process. A full understanding of the mechanisms underlying these relationships with the ultimate aim of abrogating specific steps, should lead to more targeted strategies for treatment of hormone-dependent breast cancer.