Obesity-Associated Chemotherapy Resistance in Triple-Negative Breast Cancer: The Role of Leptin-Induced Tumor-Initiating Cell Enrichment
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Gung, Joseph. Obesity-associated Chemotherapy Resistance In Triple-negative Breast Cancer: The Role of Leptin-induced Tumor-initiating Cell Enrichment. 2018. https://doi.org/10.17615/m9e3-2f89APA
Gung, J. (2018). Obesity-Associated Chemotherapy Resistance in Triple-Negative Breast Cancer: The Role of Leptin-Induced Tumor-Initiating Cell Enrichment. https://doi.org/10.17615/m9e3-2f89Chicago
Gung, Joseph. 2018. Obesity-Associated Chemotherapy Resistance In Triple-Negative Breast Cancer: The Role of Leptin-Induced Tumor-Initiating Cell Enrichment. https://doi.org/10.17615/m9e3-2f89- Last Modified
- February 26, 2019
- Creator
-
Gung, Joseph
- Affiliation: Gillings School of Global Public Health, Department of Nutrition
- Abstract
- BackgroundLeptin, a protein hormone produced by adipose tissue, is a known regulator of satiety and is also associated with inflammation, cell proliferation and differentiation. Excess adiposity, in cases of obesity, is associated with increased leptin levels, an increase in the expression of tumor-initiating cell (TIC) associated genes, as well as worse outcomes for triple-negative breast cancer (TNBC). In this study we characterize the impact of obesity-associated leptin signaling on TIC enrichment as well as determine the role of leptin on signaling on obesity-associated chemotherapy resistance.MethodsThe in vitro effects of leptin on TIC enrichment were examined by mammosphere formation assay. Met-M-Wnt cells treated with vehicle (sterile H2O) or leptin for 7 days, and the number of mammospheres was quantified. Leptin receptor, Lepr, expression in the E-Wnt, Met-M-Wnt, and MDA-MB-231 cell lines after leptin treatment was determined by quantitative RT-PCR. The role that leptin signaling has in any significant phenotypic differences between control and DIO conditions was investigated using stable knockdown of Lepr in the Met-M-Wnt cells using shRNA. Cell viability in E-Wnt, Met-M-Wnt, and MDA-MB-231 cells in response to docetaxel was assessed using MTT assays to define chemo-sensitivity. To investigate the effects of in vivo leptin signaling on chemotherapy resistance, both E-Wnt cells with Lepr knockdown and scrambled shRNA transfected cells (Ewnt-L and Ewnt-S) were transplanted into the mammary fat pads of C57BL/6 mice. The mice were randomized to a control (10% kcal from fat) or diet-induced obesity (DIO, 60% kcal from fat) diet for 15 weeks and were further randomized to vehicle (saline) or docetaxel (20 mg/kg/week x 3 doses) treatment groups. Tumor growth rates and final tumor volume were determined.ResultsIncreased leptin treatment significantly increased mammosphere formation in Met-M-Wnt cells (P<0.05) but not leptin receptor expression in these cells or E-Wnt or MDA-MB-231 cells. Stable Lepr shRNA transfection in the Met-M-Wnt cells significantly reduced Lepr expression (P<0.001). In the in vivo study, tumor growth rate in EWnt-L, but not EWnt-S tumors, was significantly reduced in DIO mice after docetaxel treatment (P<0.05). Growth rate in both tumors was significantly decreased with docetaxel treatment in the control mice (P<0.05).ConclusionsLeptin signaling may promote TIC enrichment in metastatic claudin-low breast cancer but does not upregulate leptin receptor expression in TNBC. Obesity-associated leptin signaling promotes docetaxel resistance in a model of basal-like breast cancer. Given these relationships, targeting pathways downstream of leptin signaling should be further investigated as a potential treatment option for obesity-associated chemotherapy resistance.
- Date of publication
- April 2018
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright
- Note
- Funding: SURF
- Advisor
- Hursting, Stephen
- Degree
- Bachelor of Science in Public Health
- Academic concentration
- Nutrition
- Honors level
- Honors
- Degree granting institution
- University of North Carolina at Chapel Hill
- Graduation year
- 2018
- Language
- English
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