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

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.

Responsiveness of cardiometabolic-related microbiota to diet is influenced by host genetics.

Intestinal microbial community structure is driven by host genetics in addition to environmental factors such as diet. In comparison with environmental influences, the effect of host genetics on intestinal microbiota, and how host-driven differences alter host metabolism is unclear. Additionally, the interaction between host genetics and diet, and the impact on the intestinal microbiome and possible down-stream effect on host metabolism is not fully understood, but represents another aspects of inter-individual variation in disease risk. The objectives of this study were to investigate how diet and genetic background shape microbial communities, and how these diet- and genetic-driven microbial differences relate to cardiometabolic phenotypes. To determine these effects, we used the 8 progenitor strains of the collaborative cross/diversity outbred mapping panels (C57BL/6J, A/J, NOD/ShiLtJ, NZO/HILtJ, WSB/EiJ, CAST/EiJ, PWK/PhJ, and 129S1/SvImJ). 16s rRNA profiling of enteric microbial communities in addition to the assessment of phenotypes central to cardiometabolic health was conducted under baseline nutritional conditions and in response to diets varying in atherogenic nutrient (fat, cholesterol, cholic acid) composition. These studies revealed strain-driven differences in enteric microbial communities which were retained with dietary intervention. Diet-strain interactions were seen for a core group of cardiometabolic-related microbial taxa. In conclusion, these studies highlight diet and genetically regulated cardiometabolic-related microbial taxa. Furthermore, we demonstrate the progenitor model is useful for nutrigenomic-based studies and screens seeking to investigate the interaction between genetic background and the phenotypic and microbial response to diet.