Journal Articles

Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models

June 21, 2018

Bowers LW1,2, Rossi EL1,2, McDonell SB1, Doerstling SS1, Khatib SA1, Lineberger CG1, Albright JE3, Tang X4, deGraffenried LA5, Hursting SD6,2,3. Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models. Mol Cancer Res. 2018 May;16(5):869-879. doi: 10.1158/1541-7786.MCR-17-0508. Epub 2018 Feb 16.

Author information

1 Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina.

2 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.

3 Nutrition Research Institute, University of North Carolina, Kannapolis, North Carolina.

4 Department of Biological Sciences, Michigan Technological University, Houghton, Michigan.

5 Department of Nutritional Sciences, University of Texas, Austin, Texas.

6 Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina..

Abstract

Obesity is associated with poor prognosis in triple-negative breast cancer (TNBC). Preclinical models of TNBC were used to test the hypothesis that increased leptin signaling drives obesity-associated TNBC development by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). MMTV-Wnt-1 transgenic mice, which develop spontaneous basal-like, triple-negative mammary tumors, received either a control diet (10% kcal from fat) or a diet-induced obesity regimen (DIO, 60% kcal from fat) for up to 42 weeks (n = 15/group). Mice were monitored for tumor development and euthanized when tumor diameter reached 1.5 cm. Tumoral gene expression was assessed via RNA sequencing (RNA-seq). DIO mice had greater body weight and percent body fat at termination than controls. DIO mice, versus controls, demonstrated reduced survival, increased systemic metabolic and inflammatory perturbations, upregulated tumoral CSC/EMT gene signature, elevated tumoral aldehyde dehydrogenase activity (a CSC marker), and greater leptin signaling. In cell culture experiments using TNBC cells (murine: E-Wnt and M-Wnt; human: MDA-MB-231), leptin enhanced mammosphere formation, and media supplemented with serum from DIO versus control mice increased cell viability, migration, invasion, and CSC- and EMT-related gene expression, including Foxc2, Twist2, Vim, Akt3, and Sox2 In E-Wnt cells, knockdown of leptin receptor ablated these procancer effects induced by DIO mouse serum. These findings indicate that increased leptin signaling is causally linked to obesity-associated TNBC development by promoting CSC enrichment and EMT.

Implications: Leptin-associated signals impacting CSC and EMT may provide new targets and intervention strategies for decreasing TNBC burden in obese women. Mol Cancer Res; 16(5); 869-79. ©2018 AACR.

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