Role of receptor complexes in the extranuclear actions of estrogen receptor α in breast cancer

Abstract

Our recent studies have examined the role of various receptor complexes in the mediation of rapid, extranuclear effects of estradiol. This review describes 17b-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 a (ERa). Present investigative emphasis focuses on the additional importance of ERa residing in or near the plasma membrane. A small fraction of ERa is associated with the cell membrane and mediates the rapid effects of E2. Unlike classical growth factor receptors, such as IGF-1R and EGFR, ERa 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 ERa 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.

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

“…Activation of AKT and overexpression of EGF and ERBB receptors are consistent with previous observations in MCF7-LTED cells and related breast cancer conditions (Masamura et al, 1995;Jeng et al, 1998;Shim et al, 2000;McClelland et al, 2001;Knowlden et al, 2003;Osborne et al, 2005;Yue et al, 2005;Song et al, 2006;Beeram et al, 2007;LewisWambi et al, 2008;Santen et al, 2008;Ghayad et al, 2009). Notably, ERBB2 amplification was associated with resistance to endocrine therapies (Ellis et al, 2006), and treatment with the mTOR inhibitor RAD001 increased letrozole efficacy in a neoadjuvant setting of ERa-positive breast cancer (Baselga et al, 2009).…”

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

“…This suggests that AR might be recruited to membranes by other membrane proteins, thereby facilitating the flow of signals from AR to Akt and possibly to other signaling proteins. Consistent with this idea, ER␣ was found to be capable of activating signaling from the insulin-like growth factor-1 receptor by a mechanism involving direct binding of ER␣ to the insulinlike growth factor-1R (45). Post-translational modifications, such as phosphorylation (46) or palmitoylation (47), would be another mechanism by which AR might be recruited to membrane sites.…”

Adaptation to Estradiol Deprivation Causes Up-Regulation of Growth Factor Pathways and Hypersensitivity to Estradiol in Breast Cancer Cells

“…2B, top panel) and in xenografts (data not shown) and were inhibited by the pure antiestrogen, fulvestrant. 8,11 We further demonstrated that activated MAP kinase is implicated in the enhanced growth of LTED cells since inhibitors of MAP kinase such as PD98059 or U-0126 block the incorporation of tritiated thymidine into DNA. 7 To demonstrate proof of the principle of MAP kinase participation, we stimulated activation of MAP kinase in wild type MCF-7 cells by administering TGFα (data not shown).…”