High Carbohydrate And Fat Diet Hastens Tumor Growth, Increases Pro-Inflammatory Signals And Metabolic Shifts In A Mouse Model Of Basal-Like Breast Cancer

Numerous studies have established obesity as an important risk factor for most cancers, but the mechanisms underlying the links between obesity and cancer are still being elucidated. It is known that obesity can cause destructive inflammation, which is a hallmark of cancer. This study was designed to determine the impact of different macronutrients on breast tumor growth and progression. Female C57/BL6 mice were fed a high carbohydrate plus high fat (HCHF) diet (Diet C) compared to a diet more balanced between simple carbohydrate, fat, protein and fiber (Diet D). Basal-like breast cancer tumor formation was induced using MMTV-Wnt-1 mouse mammary cells. Three weeks post-implantation (week 18), most mice were sacrificed to determine the role of diet and obesity on tumor formation and growth. Body weight, food consumption and tumor volume were measured weekly, then high-throughput approaches were used to identify macronutrient-driven, obesity-associated inflammation and metabolic markers. Compared to mice fed Diet D, the average total body weight of mice fed Diet C was 1.5 times greater after 15 weeks. Interestingly, averaged total liver weights for mice on Diet C was 4.9-fold larger (1.172 g) compared to liver weights for mice on Diet D (0.327 g). Diet C resulted in more rapid tumor growth, with tumor volumes of 126.349 m3 compared to 60.828 m3 (Diet D) at 18 weeks; and larger final tumor weights at 22 weeks (1.58 g versus 0.98 g). Protein arrays analyzed relative fold-changes in 80 pro-inflammatory cytokines, chemokines and growth factors; and Biocrates p180 kit semi-to-quantitatively measured 188 metabolites. Diet C significantly increased 79/80 cytokines, compared to 24/80 in livers of mice fed Diet D after 15 weeks. Following tumor formation 30/80 cytokines were upregulated and 7/80 were significantly downregulated on Diet C, while Diet D downregulated 18/80 but only upregulated 15/80 markers. Metabolomics data demonstrated several specific increases in acylcarnitines, amino acids, sugars and two lipid classes in mice after only one week on Diet C, some of which decreased by 10 weeks. Other metabolic shifts were only evident on Diet C 4 weeks post-implantation. In addition to the strong pro-inflammatory profile after consuming the HCHF diet (C), the increase in liver weights for these mice suggests development of a severe fatty liver disorder; and though some cytokines diminished upon tumor establishment, more markers persisted to a greater degree compared to results on the healthier diet (D). The mechanistic shifts also reflect faster-growing, larger mammary tumors in mice fed higher carbohydrate and fat content. Our study establishes a good model to better define and potentially counter-act metabolic and inflammatory consequences of detrimental macronutrient consumption linked to obesity-sensitive breast and other cancers. Citation Format: Supradeep S. Madduri, Erika T. Rezeli, Charlene M. Santos, Herman L. Freeman, Susan L. McRitchie, David R. Kirchner, Susan J. Sumner, Stephen D. Hursting, Delisha A. Stewart. High carbohydrate and fat diet hastens tumor growth, increases pro-inflammatory signals and metabolic shifts in a mouse model of basal-like breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-280.