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

Crystal C Lipsey,Ruben R Gonzalez-Perez,Lyn M Huff,Adriana Harbuzariu,Michael M Gottesman,Robert W Robey

doi:10.3390/ijms21113794

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.

Highlights

Obesity is a worldwide problem that increases the incidence and severity of many different medical conditions
This study provides evidence that high OBR mRNA expression and co-expression of leptin signaling targeted genes is associated with significantly decreased breast cancer (BC) patient survival, among those suffering from BCER−
Gene expression was analyzed on The Cancer Genome Atlas (TCGA) datasets from BC samples to construct Kaplan–Meier survival curves and determine whether there is an association between high OBR expression and BC patient survival

Summary

Introduction

Obesity is a worldwide problem that increases the incidence and severity of many different medical conditions. 13 different obesity-related cancers have been identified, including postmenopausal breast cancer (BC) [3]. Several aberrant mechanisms are believed to be involved in the development of obesity-related cancers. Among these mechanisms, the link between major proliferative pathways and excess amounts of adipose tissue has been investigated via the increased production and circulation of leptin, a 16 kDa protein adipokine [4,5,6]. Leptin binding to OBR induces the recruitment of JAK2 kinase, which in turn activates several canonical signaling responses, including the phosphorylation of STAT3 [9]. Leptin signaling upregulates Notch and its gatekeeper, the transcription factor RBP-Jk [11], and several pluripotent molecules that can induce cancer stem cell maintenance. Cancer stem cells are believed to contribute to chemoresistance and tumor relapse [10,12,13]

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Results

Conclusion