Abstract
PurposeGlycine and serine are well-known, classic metabolites of glycolysis. Here, we profiled the expression of enzymes associated with serine/glycine metabolism in different molecular subtypes of breast cancer and discuss their potential clinical implications.MethodsWe used western blotting and immunohistochemistry to examine five serine-/glycine-metabolism–associated proteins (PHGDH, PSAT, PSPH, SHMT, and GLDC) in six breast cancer cell lines and 709 breast cancer cases using tissue microarray (TMA).ResultsPHGDH and PSPH, associated with serine metabolism, were highly expressed in the TNBC cells. GLDC, associated with glycine metabolism, was highly expressed in HER-2-positive MDA-MB-453 and TNBC-related MDA-MB-435S. TMA showed that the TNBC-type breast cancer tissues highly expressed PHGDH, PSPH, and SHMT1, but not the luminal-A-type tissues (p<0.001). PSPH and SHMT1 expression in the tumor stroma of HER-2-type cancers was the highest, but the luminal-A tissues showed the lowest expression (p<0.001). GLDC was most frequently expressed in cancer cells and stroma of the HER-2-positive cancers and least frequently in TNBC (p<0.001). By Cox multivariate analysis, tumor PSPH positivity (hazard ratio [HR]: 2.068, 95% confidence interval [CI]: 1.049–4.079, p = 0.036), stromal PSPH positivity (HR: 2.152, 95% CI: 1.107–4.184, p = 0.024), and stromal SHMT1 negativity (HR: 2.142, 95% CI: 1.219–3.764, p = 0.008) were associated with short overall survival.ConclusionsExpression of serine-metabolism–associated proteins was increased in TNBC and decreased in the luminal-A cancers. Expression of glycine-metabolism–associated proteins was high in the tumor and stroma of HER-2-positive cancers.
Highlights
The ‘‘Warburg effect’’ explains a much higher rate of glycolysis followed by fermentation in the cancer cell mitochondria
The density of each protein was calculated relative to b-actin and assessed in relation to the molecular subtypes of the tested cell lines: MCF-7 and MDA-MB-361 representing the luminal type; MDA-MB-453, HER-2 type; and MDA-MB-453S, MDA-MB-231, and MDA-MB-468, triple-negative breast cancer (TNBC) type
glycine decarboxylase (GLDC) was expressed to a greater extent in the epithelial rather than in the stromal component of the luminal-B, HER-2, and TNBC types; the opposite pattern was observed in the luminal-A cancers
Summary
The ‘‘Warburg effect’’ explains a much higher rate of glycolysis followed by fermentation in the cancer cell mitochondria. According to the Warburg effect, glycolytic intermediates, especially those involved in glycine and serine metabolism, rapidly accumulate in cancer cells [1]. 3-phosphoglycerate (3PG) produced by glycolysis is oxidized to 3-phosphohydroxypyruvate (pPYR) by phosphoglycerate dehydrogenase (PHGDH), and pPYR is transaminated to phosphoserine (pSER) by phosphoserine aminotransferase (PSAT). These enzymes are highly expressed in several human tumors: PHGDH in breast cancer and melanoma [2,3] and GLDC in lung cancer [4]. They likely play important roles in tumorigenesis [2,3,4,5]
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