GPER1 promotes estrogen receptor negative breast cancer cell migration and invasion via non-genomic activation of c-Src/NF-&kgr;B/focal adhesion kinase cascade

Abstract

Abstract Breast cancer metastasis is the root cause of deaths from breast cancer. Currently, endocrine therapy resistance in estrogen receptor (ER)-positive (ER+) breast cancer remains a major clinical issue. Moreover, ER-negative (ER−) breast cancer is often associated with distant recurrence and death. G-protein-coupled ER (GPER1) participates in endocrine therapy resistance and is involved in the malignant progression of breast cancer. However, the underlying detailed mechanisms remain obscure. Here we investigated the role and mechanism of GPER1 in the activation of focal adhesion kinase (FAK) using ER+ or ER− breast cancer cell lines. In SK-Br-3 cells (ER&agr;−/&bgr;−/GPER1+), both 17&bgr;-estradiol (E2) and the GPER1 agonist G1 resulted in rapid FAK phosphorylation. This action is due to GPER1 interaction with the non-receptor tyrosine kinase c-Src and subsequent activation of nuclear factor kappa B (NF-&kgr;B) signaling. Silencing of GPER1, c-Src or the nuclear factor kappa B p65 subunit blocked E2- or G1-induced SK-Br-3 cell migration and invasion. In MCF-7 cells (ER&agr;+/&bgr;+/GPER1+), silencing of GPER1, but not ER&agr; or ER&bgr;, abolished FAK phosphorylation induced by E2 or G1. In MDA-MB-231 cells (ER&agr;−/&bgr;+/GPER1−), E2 or G1 was also unable to stimulate E2-induced FAK phosphorylation. However, E2 and G1 regained the ability to induce FAK phosphorylation under conditions of overexpression of GPER1. In conclusion, we demonstrated that GPER1, but not ER&agr; or ER&bgr;, mediates FAK phosphorylation induced by E2 via the c-Src/p65 signaling pathway, which enhances cell migration and invasion. These findings may shed light on novel therapeutic strategies based on GPER1/FAK signaling pathways in suppression of breast cancer metastasis.