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.
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..
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.