Microbiology, Biochemistry, and Immunology, GEBS, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Mol Sci. 2020 May 27;21(11):3794. doi: 10.3390/ijms21113794.
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.
雌激素受体阴性乳腺癌（BCER-）主要采用化疗治疗。瘦素信号可能影响 BCER-的进展，但它对患者生存和化疗耐药性的影响尚不清楚。我们假设瘦素信号通过诱导化疗耐药相关基因的表达，从而降低 BCER-患者的生存率。从癌症基因组图谱（TCGA）mRNA 数据中确定了瘦素受体（OBR）、瘦素靶向基因（CDK8、NANOG 和 RBP-Jk）的表达与 BC 患者生存的相关性。在对化疗药物反应不同的三阴性乳腺癌（TNBC）细胞中，研究了瘦素诱导的增殖和化疗耐药相关分子的表达。通过 RNA-Seq 分析了 TNBC 中的瘦素诱导基因表达。使用 OBR 抑制剂（shRNA 和肽）评估了瘦素作用的特异性。结果表明，OBR 和瘦素靶向基因的表达与 BCER-患者生存率降低相关。重要的是，这些基因的共表达也与化疗失败相关。瘦素信号增加了与肿瘤发生和化疗耐药相关的基因（ABCB1、WNT4、ADHFE1、TBC1D3、LL22NC03、RDH5 和 ITGB3）的表达，并损害了 TNBC 细胞的化疗效果。OBR 抑制使 TNBC 对化疗药物重新敏感。总之，OBR 和瘦素靶向基因的共表达可作为预测 BCER-患者生存和耐药的指标。靶向 OBR 信号可能提高化疗疗效。
