Obesity is associated with increased cancer risk and cancer-associated mortality1,2. Hypertriglyceridemia (HTG), a component of the metabolic syndrome which frequently co-exists with obesity, has been associated with increased breast cancer risk and mortality in triple negative breast cancer (TNBC)3,4. To determine if HTG is causally related to enhanced TNBC progression in the absence of other obesity-associated characteristics, TNBC growth and metastasis in a mouse model of HTG was examined. Mice overexpressing human apolipoprotein C3 (AC3) were backcrossed onto FVB/N background and crossed with recombination-activating gene 1 (Rag1) knockout mice to generate immunodeficient HTG mice. AC3 mice relative to wild-type (WT) littermates showed a 20-fold higher circulating triglycerides (p < 0.0001) and elevated very low density lipoprotein (VLDL) cholesterol (p = 0.001). No differences in body weight, body composition, blood glucose or plasma insulin levels were observed between the two groups, allowing for investigation on the influence of HTG on TNBC without confounders such as hyperinsulinemia or hyperglycemia. AC3 mice orthotopically implanted with the mouse mammary tumor cell line, Mvt1, showed both increased tumor growth (AC3 vs WT: 1157.0 ± 84.2 vs 707.2 ± 58.6 mm3, p = 0.0009) and lung metastasis (AC3 vs WT: 57.3 ± 3.0 vs 32.9 ± 5.3 mm3, p = 0.001) relative to WT mice. Immunodeficient Rag1/AC3 mice likewise, showed increased tumor growth compared to WT controls when implanted with human TNBC MDA-MB-231 cells (AC3 vs WT: 363.2 ± 113.9 vs 92.95 ± 16.2 mm3, p = 0.038). To investigate how HTG affects tumor lipid metabolism, serum and tumors from both groups were analyzed by liquid chromatography/mass spectrometry. Total alkyl-acyl, di-acyl-phosphatidylcholines and sphingomyelin concentrations were higher in the serum of AC3 mice relative to WT. In contrast, no overall difference in tumor phospholipid or acylcarnitine content was noted between AC3 and WT mice, suggesting no difference in fatty acid oxidation in the setting of HTG. Mvt1 tumors from AC3 and WT mice were analyzed by RNA sequencing. Decreased expression of genes associated with cholesterol synthesis (Fdft1, Pvmk, Acss2) were found in tumors from AC3 mice. Tumors from AC3 mice also showed decreased protein expression of LDLR, which is associated with LDL cholesterol uptake. Overall, these findings suggest that HTG, independently of other obesity-associated characteristics such as hyperinsulinemia and hyperglycemia, leads to changes in intracellular lipid metabolism and promotes TNBC progression.
References: 1Chan, D. S. M. et al. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.25, 1901-1914 (2014). 2Pierobon, M. & Frankenfeld, C. L. Breast Cancer Res. Treat.137, 307-314 (2013). 3Lofterød, T. et al. BMC Cancer18, 654 (2018).4Goodwin, P. J. et al. Nutr. Cancer27, 284-292 (1997).