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

• Published in: Molecular cancer research Vol. 16; no. 5; pp. 869 - 879
• Main Authors: Bowers, Laura W., Rossi, Emily L., McDonell, Shannon B., Doerstling, Steven S., Khatib, Subreen A., Lineberger, Claire G., Albright, Jody E., Tang, Xiaohu, deGraffenried, Linda A., Hursting, Stephen D.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.05.2018
• Subjects: Aldehyde dehydrogenase; Animal models; Animals; Body fat; Body weight; Breast cancer; Cancer; Cell culture; Cell Line, Tumor; Cell migration; Culture media; Diet; EMT gene; Enrichment; Epithelial-Mesenchymal Transition; Female; Gene expression; Gene sequencing; Humans; Inflammation; Leptin - metabolism; Medical prognosis; Mesenchyme; Mice; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Obesity; Obesity - metabolism; Ribonucleic acid; RNA; Rodents; Signal Transduction; Signaling; Stem cells; Transgenic mice; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumors; Wnt protein
• ISSN: 1541-7786; 1557-3125; 1557-3125
• DOI: 10.1158/1541-7786.MCR-17-0508

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.