Estradiol treatment of human breast cancer cells stimulates GPER1-dependent formation of integrin alpha5 beta1:fibronectin (FN):phosphorylated SHC1 complexes in a SRC- and G-protein beta gamma-dependent fashion (Quinn et al, 2009). Formation of integrin:fibronectin fibrils has been shown to enhance anchorage independent growth (Salnier et al, 1996; Qiao et al, 2000; Quinn et al, 2009). Formation of a fibronectin:integrin matrix is required for estradiol-stimulated EGFR phosphorylation, and consistent with this, EGFR phosphorylation is inhibited after treatment of cells with either soluble FN peptide fragments or antibody that blocks the integrin alpha5beta1:fibronectin interaction (Quinn et al, 2009; reviewed in Prossnitz and Barton, 2014). Although SHC is known to have roles downstream of activated EGFR, EGFR phosphorylation after estradiol stimulation is abrogated in the inactive SHC Y317F mutant, suggesting that SHC acts upstream of EGFR in this pathway. In contrast, SHC phosphorylation is not required for the interaction with integrin alpha5beta1 (Quinn et al, 2009).