Abstract
BackgroundThe 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.MethodsA 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).ResultsThe 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).ConclusionsDifferences 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.
Highlights
Breast cancer has a high morbidity and mortality, mainly because it can metastasize to distant organs
The proportion of cases with estrogen receptor (ER) positivity and progesterone receptor (PR) positivity was higher among those with bone and liver metastases than in those with metastasis to other sites (p < 0.001), and HER-2 positivity was higher among cases of brain metastasis compared to other sites (p = 0.017)
Luminal A type tumors were more common among patients with bone and liver metastasis, while the proportion of tripe negative breast cancer (TNBC) was higher among cases of brain and lung metastasis (p < 0.001) (Table 2)
Summary
Breast cancer has a high morbidity and mortality, mainly because it can metastasize to distant organs. The main metastatic sites from breast cancer are the lung, bone, brain, and liver [1,2]. Because different cancers display distinct metastatic patterns, the seed and soil hypothesis has been proposed, which dictates that the specific tumor (seed) can survive only in specific visceral organs (soil) [10]. Metastatic breast cancer cells show different characteristics according to the metastatic site. Metastatic breast cancer is likely to display distinct characteristics according to metastatic site. 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
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