Blotting, Western ; Breast Neoplasms/classification* ; Breast Neoplasms/enzymology* ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Disease-Free Survival ; Female ; Glycine/metabolism* ; Glycolysis ; Humans ; Middle Aged ; Multivariate Analysis ; Neoplasm Proteins/metabolism ; Phenotype ; Serine/metabolism*
Abstract
PURPOSE:
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.
METHODS:
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).
RESULTS:
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.
CONCLUSIONS:
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.