Figure 9

Role of GPR30 in the development of tamoxifen resistance. Long-term endocrine therapy can inhibit ERα-regulated gene transcription in hormone-dependent breast cancer; whereas tamoxifen-facilitated translocation of GPR30 to the cell membrane enhances crosstalk with EGFR signaling through the Gβγ subunit of GPR30. However, when treated with GPR30 plus tamoxifen, GPR30’s Gα subunit attenuates cAMP suppression of Erk1/2 phosphorylation of an EGF downstream factor. As tamoxifen is an agonist for GPR30, endocrine therapy can stimulate GPR30/EGFR crosstalk, leading to cell growth. When this activation effect exceeds ERα inhibition, breast cancer progresses under tamoxifen treatment. Interrupting direct crosstalk between GPR30 and EGFR by use of a GPR30-specific antagonist (G15) induces both cytocidal action in vitro and an antitumor effect in vivo. Targeted therapy with GPR30 could restore endocrine therapy response in tamoxifen-resistant breast cancer. EGFR, epidermal growth factor receptor; ER, estrogen receptor; GPR30, G-protein coupled receptor 30.