Mechanism Of GRP30 Induces Breast Cancer Cells Autophagy And Resistance To Tamoxifen

Tamoxifen(TAM)resistance constitutes a challenge in managing estrogen receptor(ER)α+ breast cancer patient’s therapy.G-proteincoupled estrogen receptor(GPR30/GPER),which reportedly initiates TAM resistance in ERα+/GPR30+ breast cancers,is detected in the breast cancer microenvironment,especially in cancer-associated fibroblasts(CAFs).Considering that GPR30 can mediate transcriptional regulation,a microarray strategy was applied to identify GPR30 downstream target gene-HMGB1 in immortalized CAFs derived from primary breast cancer samples.We next found that increasing extracellular HMGB1 secretion can be reduced by blocking PI3K/AKT signaling using G15 or LY294002.Moreover,GPR30-induced HMGB1 upregulation can trigger MEK/ERK signal pathway,increasing autophagic behavior which protects cancer cells from TAM-induced apoptosis,mimicking the recombinant HMGB1-mediated resistance potential of the cancer cell to TAM.And that,the utilization of U0126 to block MEK/ERK signaling decreased the autophagic behavior and resistance ability of cancer cells to TAM.Lastly,GPR30 induced TAM resistance via HMGB1 was confirmed by experiment in vivo.Overall,TAM upregulated HMGB1 expression and secretion in CAFs via GPR30/PI3K/AKT signaling,and the secreted HMGB1 induced autophagy to enhance TAM resistance in MCF-7 cells in an ERK-dependent manner.Thus,targeting GPR30 and downstream cascades may be an effective strategy to attenuate the resistance of ERα-positive breast tumors to endocrine therapy.