Leptin Signaling Affects Survival and Chemoresistance of Estrogen Receptor Negative Breast Cancer

Abstract

Estrogen-receptor-negative breast cancer (BCER−) is mainly treated with chemotherapeutics. Leptin signaling can influence BCER− progression, but its effects on patient survival and chemoresistance are not well understood. We hypothesize that leptin signaling decreases the survival of BCER− patients by, in part, inducing the expression of chemoresistance-related genes. The correlation of expression of leptin receptor (OBR), leptin-targeted genes (CDK8, NANOG, and RBP-Jk), and breast cancer (BC) patient survival was determined from The Cancer Genome Atlas (TCGA) mRNA data. Leptin-induced expression of proliferation and chemoresistance-related molecules was investigated in triple-negative BC (TNBC) cells that respond differently to chemotherapeutics. Leptin-induced gene expression in TNBC was analyzed by RNA-Seq. The specificity of leptin effects was assessed using OBR inhibitors (shRNA and peptides). The results show that OBR and leptin-targeted gene expression are associated with lower survival of BCER− patients. Importantly, the co-expression of these genes was also associated with chemotherapy failure. Leptin signaling increased the expression of tumorigenesis and chemoresistance-related genes (ABCB1, WNT4, ADHFE1, TBC1D3, LL22NC03, RDH5, and ITGB3) and impaired chemotherapeutic effects in TNBC cells. OBR inhibition re-sensitized TNBC to chemotherapeutics. In conclusion, the co-expression of OBR and leptin-targeted genes may be used as a predictor of survival and drug resistance of BCER− patients. Targeting OBR signaling could improve chemotherapeutic efficacy.

Keywords

• estrogen receptor negative breast cancer survival
• leptin
• leptin antagonist
• obesity-related cancer
• chemoresistance