Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-02, Vol.82 (4), p.665-680
• Main Authors: Liao, Chengheng, Glodowski, Cherise Ryan, Fan, Cheng, Liu, Juan, Mott, Kevin R, Kaushik, Akash, Vu, Hieu, Locasale, Jason W, McBrayer, Samuel K, DeBerardinis, Ralph J, Perou, Charles M, Zhang, Qing
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biphenyl Compounds - pharmacology; Carboplatin - administration & dosage; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Gene Expression Profiling - methods; Humans; Metabolomics - methods; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Molecular Targeted Therapy - methods; Paclitaxel - administration & dosage; Signal Transduction - drug effects; Signal Transduction - genetics; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Xenograft Model Antitumor Assays - methods
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-21-2745

Metabolic dysregulation is a prominent feature in breast cancer, but it remains poorly characterized in patient tumors. In this study, untargeted metabolomics analysis of triple-negative breast cancer (TNBC) and patient with estrogen receptor (ER)-positive breast cancer samples, as well as TNBC patient-derived xenografts (PDX), revealed two major metabolic groups independent of breast cancer histologic subtypes: a "Nucleotide/Carbohydrate-Enriched" group and a "Lipid/Fatty Acid-Enriched" group. Cell lines grown in vivo more faithfully recapitulated the metabolic profiles of patient tumors compared with those grown in vitro. Integrated metabolic and gene expression analyses identified genes that strongly correlate with metabolic dysregulation and predict patient prognosis. As a proof of principle, targeting Nucleotide/Carbohydrate-Enriched TNBC cell lines or PDX xenografts with a pyrimidine biosynthesis inhibitor or a glutaminase inhibitor led to therapeutic efficacy. In multiple in vivo models of TNBC, treatment with the pyrimidine biosynthesis inhibitor conferred better therapeutic outcomes than chemotherapeutic agents. This study provides a metabolic stratification of breast tumor samples that can guide the selection of effective therapeutic strategies targeting breast cancer subsets. In addition, we have developed a public, interactive data visualization portal (http://brcametab.org) based on the data generated from this study to facilitate future research. A multiomics strategy that integrates metabolic and gene expression profiling in patient tumor samples and animal models identifies effective pharmacologic approaches to target rapidly proliferating breast tumor subtypes.