Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/ijms21113794
Keywords
estrogen receptor negative breast cancer survival; leptin; leptin antagonist; obesity-related cancer; chemoresistance
Funding
- MSM/Tuskegee University/UAB Cancer Center partnership grant [5U54CA118638]
- PC SPORE Grant from UAB [1G12RR026250-03, NIH RR 03034, 1C06 RR18386]
- National Institute of General Medical Sciences, National Institutes of Health [R25GM058268]
- Intramural Research Program of the N.I.H., the laboratory of Michael M. Gottesman (Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute)
- NATIONAL CANCER INSTITUTE [ZIABC010830] Funding Source: NIH RePORTER
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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.
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