Site-specific metabolic phenotypes in metastatic breast cancer

Background: The purpose of this study was to examine the expression of metabolism-related proteins according to metastatic site in metastatic breast cancer and to assess the implication of site-specific differential expression. Methods: A tissue microarray containing 162 cases of metastatic breast cancer (52 lung metastasis, 47 bone metastasis, 39 brain metastasis, and 24 liver metastasis) was constructed. It was subject to immunohistochemical staining of the following proteins: Glycolysis-related: Glut-1, hexolinase II, carbonic anhydrase (CA) IX, and monocarboxylate transporter (MCT) 4; glutaminolysis-related: glutaminase (GLS) 1, glutamate dehydrogenase (GDH), and amino acid transporter (ASCT) 2; mitochondrial metabolism-related: ATP synthase, succinate dehydrogenase (SDH)A, and SDHB; and serine/glycine metabolism related: phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT), phosphoserine phosphatase (PSPH), glycine decarboxylase (GLDC), and serine hydroxymethyltransferase (SHMT). Results: The expression levels of glycolysis-related-proteins (Glut-1, hexokinase II, CAIX, and MCT4) differed according to metastatic site, with higher expression seen in the brain and lower expression in the bone and liver (p < 0.001, 0.001, 0.009, and <0.001, respectively). Differences in metabolic phenotype were analyzed according to metastasis site. Glycolysis type was most frequently encountered in the brain and lung (p < 0.001). In univariate analysis, the factors associated with shorter overall survival were CAIX positivity (p = 0.044), PSPH positivity (p = 0.045), and SHMT1 positivity (p = 0.002), as well as serine/glycine type (p = 0.041). Conclusions: Differences in metabolic features according to metastatic site were seen in metastatic breast cancer, with the glycolysis phenotype found predominantly in the brain and lung and the non-glycolysis phenotype in the bone and liver.