In this study, we examined differential expression patterns of some of the enzymes associated with serine/glycine metabolism in the different molecular subtypes of the breast cancer in separate histopathological tumor compartments and investigated their likely clinical implications. Enzymes associated with serine metabolism, including PHGDH and PSPH were highly expressed in the TNBC cell lines and tissues, but not significantly expressed in the luminal-A subtype. Previous studies have reported increased expression of PHGDH especially in the ER-negative cancers, showing an expression rate about 70%. We also confirmed that PHGDH was highly expressed in the TNBC subtype, representative ER-negative breast cancers. PHGDH was expressed in 68.1% of the ER-negative cancers in comparison with 18.5% in the ER-positive cancers and was associated with high histologic grading, ER negativity, PR negativity, and high Ki-67 LI, which are known as poor prognosticators. Similar to PHGDH, PSPH was frequently expressed in the TNBC Dinaciclib subtype and correlated with high histopathological grading, ER negativity, PR negativity, and high Ki-67 LI. Thus, we hypothesize that a breast cancer subset with high expression of enzymes associated with serine metabolism could present with an aggressive behavior. It is likely that metabolic demand for serine metabolites may increase as the overall metabolic demand increases in breast cancers with aggressive pathological behavior. Previous reports demonstrated that the glycolysis-associated enzymes, such as Glut-1, CA9, and MCT4, were distinctly expressed in different molecular subtypes: high in the TNBC and basal-like, but low in the luminal-A subtype. This study showed that expression of Glut-1 and CA9 were linked to PHGDH and PSPH expression, which could be explained because serine metabolites serve as glycolytic intermediates. Thus, serine metabolism provides a-ketoglutarate, a TCA-cycle intermediate, to cancer cells instead of serine itself, leading to acceleration of mitochondrial metabolism using excess a-ketoglutarate by highly expressed enzymes which drive mitochondrial energy metabolism. Similar to PHGDH and PSPH, SHMT1 was highly expressed in the TNBC subtype and lowest in the luminal-A subtype. As previously reported, glycine metabolism is key in accelerating cancerous cell proliferation; we believe that high SHMT1 levels in the TNBC subtype ensures high proliferative capacity, showing the highest Ki-67 LI among other molecular subtypes. GLDC was also expressed at differing levels in different molecular subtypes of breast cancer. The highest GLDC expression was found in the HER-2 and the lowest in the TNBC subtype, in contrast to enzymes involved in the serine metabolism. High GLDC levels have been reported in several human cancers, including non-small-cell lung carcinoma, ovarian cancer, and germ-cell tumors; however, GLDC levels have not been studied in breast cancer. The precise mechanism of increased GLDC in HER-2 subtype could not be postulated, but GLDC levels were previously examined in MCF10A cells after oncogenic transformation by KRASG12D, PIK3CAE545K, or MYCT58A.