Tumor Lipid Signatures Are Descriptive of Acquisition of Therapy Resistance in an Endocrine-Related Breast Cancer Mouse Model

The lipid metabolism adaptations of estrogen and progesteronereceptor-positivebreast cancer tumors from a mouse syngeneic model are investigatedin relation to differences across the transition from hormone-dependent(HD) to hormone-independent (HI) tumor growth and the acquisitionof endocrine therapy (ET) resistance (HIR tumors). Results are articulatedwith reported polar metabolome results to complete a metabolic pictureof the above transitions and suggest markers of tumor progressionand aggressiveness. Untargeted nuclear magnetic resonance metabolomicswas used to analyze tumor and mammary tissue lipid extracts. Tumorprogression (HD-HI-HIR) was accompanied by increased nonesterifiedcholesterol forms and phospholipids (phosphatidylcholine, phosphatidylethanolamine,sphingomyelins, and plasmalogens) and decreased relative contentsof triglycerides and fatty acids. Predominating fatty acids becameshorter and more saturated on average. These results were consistentwith gradually more activated cholesterol synthesis, & beta;-oxidation,and phospholipid biosynthesis to sustain tumor growth, as well asan increase in cholesterol (possibly oxysterol) forms. Particularcompound levels and ratios were identified as potential endocrinetumor HD-HI-HIR progression markers, supporting new hypotheses toexplain acquired ET resistance.