Integrated Metabolic and Gene Expression Profiling Reveals New Therapeutic Modalities for Rapidly Proliferating Breast Cancers

Abstract Metabolic dysregulation, although a prominent feature in breast cancer, remains undercharacterized in patient tumors. By performing untargeted metabolomics analyses on triple-negative breast cancer (TNBC) and Estrogen Receptor (ER) positive patient breast tumors, as well as TNBC patient-derived xenografts (PDXs), we identified two major metabolic groups independent of breast cancer histological subtypes: a “Nucleotide/Carbohydrate-Enriched” group and a “Lipid/Fatty Acid-Enriched” group. Cell lines grown in vivo more faithfully recapitulate the metabolic profiles of patient tumors. Integrated metabolic and gene expression analyses reveal genes that strongly correlate with metabolic dysregulation and predict patient prognosis. As a proof-of-principle, targeting Nucleotide/Carbohydrate-Enriched TNBC cell line or PDX xenografts with a pyrimidine biosynthesis inhibitor, and/or a glutaminase inhibitor, led to therapeutic efficacy. In addition, the pyrimidine biosynthesis inhibitor presents better therapeutic outcomes than chemotherapy agents in multiple murine TNBC models. Our study provides a new stratification of breast tumor samples based on integrated metabolic and gene expression profiling, which guides the selection of newly effective therapeutic strategies targeting rapidly proliferating breast cancer subsets. In addition, we develop a public, interactive data visualization portal (http://brcametab.org) based on the data generated from this study.