Mechnisms Of ObRb Downreg?lation Increases Breast Cancer Cell Sensitivity To Tamoxifen

Leptin is a potent adipokine that plays an important role in the progression of breast cancer and interferes with the action of tamoxifen.We investigated the molec?lar mechanism underlying the effect of leptin on tamoxifen resistance in breast cancer cells that express leptin receptor(Ob Rb),and evaluated the impact of ObRb suppression on tamoxifen treatment in MCF-7 and tamoxifen-resistant(TAM-R)cells.Leptin-induced signaling pathway activation was examined by qRT-PCR and western blotting.C hromatin immunoprecipitation assays were performed to further examine the binding of estrogen receptor(ER)? on the promoter of cyclin D1(CCND1)gene.The effects of combined ObRb knockdown and tamoxifen treatment were evaluated in MCF-7 and TAM-R cells.We found the enhanced proliferation effects induced by leptin were related to extracell?lar signal-reg?lated kinase(ERK)1/2 and signal transducers and activators of transcr iption(STAT)3 signaling pathway activation and CCND1 upreg?lation.Leptin enhanced CCND1 gene transcription by inducing the binding of ER? the promoter of CCND1 gene.ObRb knockdown significantly enhanced the inhibitory effects of tamoxifen on TAM-R cell proliferation and survival.This study suggested that Long-term endocrine therapy facilitates leptin and Ob Rb overexpression in breast cancer cells,which attenuates the inhibitory effect of tamoxifen by activating both the ERK1/2 and STAT3 signaling pathways and upreg?lating CCND1 gene expression.Combination therapy involving ObRb knockdown and tamoxifen treatment may be an alternative therapeutic option for tamoxifen-resistant breast cancer.