Abstract
BackgroundCancer cells are characterized by aberrant phosphatidylcholine (PC) metabolism. PC can be synthesized de novo or absorbed from diet, after digestion, by the intestinal enterocytes. Here, we investigated the association of dietary intake of PC and breast cancer development in mice. MethodsWe used tandem mass spectrometry methods to quantitate PC content of various fat sources used to manufacture rodent diets. Rodent diets were then formulated with either casein or amino acids in place of casein. To test the effects of dietary PC on tumor growth we fed low density lipoprotein receptor-null (LDLR–/–) mice high fat diets formulated with casein (high PC) or amino acids in place of casein (low PC). Endogenous PC biosynthesis and levels of total circulated plasma PC was monitored using stable isotope tracer choline and mass spectrometry analysis. Tumors were induced in mice after 12 weeks of high fat diet feeding. Since PC-derived molecules are important transducers of mitogenic signals, we tested the effects of inhibiting production of lysophosphatidic acid (LPA) using a recently described autotaxin (ATX) inhibitor. Finally, plasma inflammatory cytokine levels were analyzed to determine the effects of diets and ATX inhibition on systemic cytokine milieu. ResultsWe found that casein is the main source of PC when present in rodent diets. Replacing casein with amino acids increased the relative proportion of endogenously biosynthesized PC in mouse plasma. Compared to diets containing casein, amino acid-defined diets decreased primary tumor growth in the hyperlipidemic estrogen-receptor positive E0771 breast cancer mouse model. Inhibition of autotaxin with the potent inhibitor PAT-505 did not attenuate breast cancer development in these hyperlipidemic mice. Further, replacing casein with amino acids or treatment with PAT-505 significantly reduced systemic markers of inflammation. ConclusionOur results show that casein is a significant source of PC when present in rodent diets. Diets formulated with amino acids in place of casein have higher proportion of circulating PC from the endogenous biosynthetic pool. Casein-containing high fat diets promote primary breast tumor development in mice through mechanisms that involve systemic inflammation but is independent of LPA production by autotaxin.
Paternal programming of breast cancer risk in daughters in a rat model: opposing effects of animal- and plant-based high-fat diets