Differential expression of enzymes associated with serine/glycine metabolism in different breast cancer subtypes.

Abstract

Glycine 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. We 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). PHGDH 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. Expression 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.