Impact of Tumor Microenvironment and Epithelial Phenotypes on Metabolism in Breast Cancer

• Published in: Clinical cancer research Vol. 19; no. 3; pp. 571 - 585
• Main Authors: BRAUER, Heather Ann, MAKOWSKI, Liza, HOADLEY, KatherineA, CASBAS-HERNANDEZ, Patricia, LANG, Lindsay J, ROMAN-PEREZ, Erick, D'ARCY, Monica, FREEMERMAN, Alex J, PEROU, Charles M, TROESTER, Melissa A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-02-2013
• Subjects: Adult; Aged; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cluster Analysis; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Glucose - metabolism; Glucose Transporter Type 1 - metabolism; Gynecology. Andrology. Obstetrics; Hepatocyte Growth Factor - metabolism; Humans; Mammary gland diseases; Medical sciences; Metabolic Networks and Pathways; Metabolome; Metabolomics; Middle Aged; Neoplasm Grading; Neoplasm Staging; Pharmacology. Drug treatments; Phenotype; Stromal Cells - metabolism; Tumor Microenvironment; Tumors; Mammary gland diseases; Phenotype; Breast disease; Cell microenvironment; Breast cancer; Malignant tumor; Pharmacokinetics; Metabolism; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-2123

Cancer cells have altered metabolism, with increased glucose uptake, glycolysis, and biomass production. This study conducted genomic and metabolomic analyses to elucidate how tumor and stromal genomic characteristics influence tumor metabolism.
Thirty-three breast tumors and six normal breast tissues were analyzed by gene expression microarray and by mass spectrometry for metabolites. Gene expression data and clinical characteristics were evaluated in association with metabolic phenotype. To evaluate the role of stromal interactions in altered metabolism, cocultures were conducted using breast cancer cells and primary cancer-associated fibroblasts (CAF).
Across all metabolites, unsupervised clustering resulted in two main sample clusters. Normal breast tissue and a subset of tumors with less aggressive clinical characteristics had lower levels of nucleic and amino acids and glycolysis byproducts, whereas more aggressive tumors had higher levels of these Warburg-associated metabolites. While tumor-intrinsic subtype did not predict metabolic phenotype, metabolic cluster was significantly associated with expression of a wound response signature. In cocultures, CAFs from basal-like breast cancers increased glucose uptake and basal-like epithelial cells increased glucose oxidation and glycogen synthesis, suggesting interplay of stromal and epithelial phenotypes on metabolism. Cytokine arrays identified hepatocyte growth factor (HGF) as a potential mediator of stromal-epithelial interaction and antibody neutralization of HGF resulted in reduced expression of glucose transporter 1 (GLUT1) and decreased glucose uptake by epithelium.
Both tumor/epithelial and stromal characteristics play important roles in metabolism. Warburg-like metabolism is influenced by changes in stromal-epithelial interactions, including altered expression of HGF/Met pathway and GLUT1 expression.