Epidermal Growth Factor Receptor and Tyrosine Phosphorylation of Estrogen Receptor

Abstract

Activation of estrogen receptor-alpha (ERalpha) by growth factors in the absence of estrogen is a well-documented phenomenon. To study further this process of ligand-independent receptor activation, COS-7 cells without ER were transfected with both ER and epidermal growth factor receptor (EGFR). In the absence of estrogen, epidermal growth factor (EGF) stimulated rapid tyrosine phosphorylation of ER in transfected COS-7 cells. Similarly, in MCF-7 breast cancer cells that have natural expression of ER and EGFR, EGF promoted acute phosphorylation of serine and tyrosine residues in ER, and a direct interaction between ER and EGFR after treatment with EGF was found. In confirmation of a direct interaction between ER and EGFR, activation of affinity-purified EGFR tyrosine kinase in vitro stimulated the phosphorylation of recombinant ER. The cross-communication between EGFR and ER appears to promote significant stimulation of cell proliferation and a reduction in the apoptotic loss of those cells that express both receptor signaling pathways. However, COS-7 cells transfected with both ER and EGFR show minimal stimulation of classical estrogen response element (ERE)-dependent transcriptional activity after stimulation by EGF ligand. This suggests that the proliferative and antiapoptotic activity of EGF-induced ER activation may be dissociated from ERE-dependent transcriptional activity of the ER.

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

“…In recent years, much evidence has shown that in multiple cell types under different experimental conditions, steroid receptors directly interact with several signaling effectors and trigger various biological effects. In addition to Src, these effectors include calmodulin (Castoria et al, 1988), the regulatory subunit of the phosphoinositide 3-kinase, p85a (Simoncini et al, 2000;Castoria et al, 2001), Shc (Song et al, 2002), modulator of non genomic activity of receptor (Wong et al, 2002), protein kinase Cz (Castoria et al, 2004), EGF receptor (Marquez et al, 2001;Migliaccio et al, 2005), and many other signaling or signaling-related proteins. Therefore, approaches similar to those followed in this report, that is, recognition of new receptor/signaling effector interactions and identification of new inhibitors of such interactions, could enable us to specifically inhibit different hormone actions mediated by signal transducing pathways in multiple cell types and in different pathological conditions.…”

Epidermal Growth Factor Induces WISP-2/CCN5 Expression in Estrogen Receptor-α-Positive Breast Tumor Cells through Multiple Molecular Cross-talks

“…A well-studied phosphorylation site in ER-a is Ser 118 (28). Both estrogen and EGF are able to enhance phosphorylation of ER-a at Ser 118 residue in various cell lines (28,35,43,45,66). EGF-induced acute phosphorylation of ER-a may be associated with the molecular cross-talk between ER and EGFR in MCF-7 cells (35,36).…”

“…Both estrogen and EGF are able to enhance phosphorylation of ER-a at Ser 118 residue in various cell lines (28,35,43,45,66). EGF-induced acute phosphorylation of ER-a may be associated with the molecular cross-talk between ER and EGFR in MCF-7 cells (35,36). Consistent with previous studies, our findings indicate that EGF enhances phosphorylation of ER-a at Ser 118 in MCF-7 cells parallel with WISP-2/CCN5 up-regulation (Fig.…”

“…The involvement of the ER in estrogen-like actions of EGF in rat uterus and breast tumor cells has been established (24,25,27,(34)(35)(36)(37). The data described in the preceding section led us to investigate if the ER is involved in regulation of WISP-2/CCN5 expression by EGF in MCF-7 cells.…”

Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival

“…Another potential role player in endometrial cancer aetiology is the epidermal growth factor (EGF). This protein can activate ESR1 and acts as a potent mitogen for epithelial cells (Nelson et al, 1991;Ignar-Trowbridge et al, 1992;Curtis et al, 1996;Dickson and Lippman, 1998;Marquez et al, 2001). We intended to study common variation in both the ESR1 (MIM 133430) and EGF (MIM 131530) genes in relation to endometrial cancer risk, myometrial invasion and endometrial cancer survival.…”