Dietary Energy Balance Modulates Epithelial-to-Mesenchymal Transition and Tumor Progression in Murine Claudin-Low and Basal-like Mammary Tumor Models

摘要: Using novel murine models of claudin-low and basal-like breast cancer, we tested the hypothesis that diet-induced obesity (DIO) calorie restriction (CR) differentially modulate progression these aggressive cancer subtypes. For model development, characterized two cell lines, "mesenchymal (M)-Wnt" "epithelial (E)-Wnt," derived from MMTV-Wnt-1 transgenic mouse mammary tumors. M-Wnt, relative to E-Wnt, cells were tumor-initiating (TIC)-enriched (62% vs. 2.4% CD44(high)/CD24(low)) displayed enhanced ALDEFLUOR positivity, epithelial-to-mesenchymal transition (EMT) marker expression, mammosphere-forming ability, migration, invasion, tumorigenicity (P < 0.001; each parameter). M-Wnt E-Wnt clustered with tumors, respectively, in gene expression profiles recapitulated tumors when orthotopically transplanted into ovariectomized C57BL/6 mice. To assess effects energy balance interventions on tumor EMT, mice administered DIO, control, or CR diets for 8 weeks before orthotopic transplantation (for line, n = 20 per diet) continued their 6 while growth was monitored. Relative DIO 0.01), but not progression; upregulated EMT- TIC-associated markers including N-cadherin,fibronectin, TGFβ, Snail, FOXC2, Oct4 0.05, each); increased intratumoral adipocytes. Conversely, suppressed 0.02, each) inhibited EMT adipocyte accumulation. Thus, dietary pathway components may represent targets breaking obesity-breast link, particularly preventing and/or controlling TIC-enriched subtypes such as cancer.