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.

• Authors: Crystal C Lipsey, Adriana Harbuzariu, Robert W Robey, Lyn M Huff, Michael M Gottesman, Ruben R Gonzalez-Perez
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 11 (May 27 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32471192 (Publication Type: Journal Article)

Chemical References

• Immunoglobulin J Recombination Signal Sequence-Binding Protein
• Leptin
• NANOG protein, human
• Nanog Homeobox Protein
• Receptors, Estrogen
• Receptors, Leptin
• CDK8 protein, human
• Cyclin-Dependent Kinase 8

Topics

• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line
• Cell Line, Tumor
• Cyclin-Dependent Kinase 8 (genetics, metabolism)
• Drug Resistance, Neoplasm
• Female
• Humans
• Immunoglobulin J Recombination Signal Sequence-Binding Protein (genetics, metabolism)
• Leptin (metabolism)
• Nanog Homeobox Protein (genetics, metabolism)
• Receptors, Estrogen (genetics)
• Receptors, Leptin (genetics, metabolism)
• Signal Transduction
• Survival Analysis