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  • Several enzymes in serine and glycine metabolism have been

    2024-04-18

    Several enzymes in serine and glycine metabolism have been proposed as biomarkers for cancer stage and prognosis. Phosphoglycerate dehydrogenase (PHGDH), phosphoserine phosphatase (PSPH), and serine hydroxymethyltransferase (SHMT) levels are high in TNBC and low in luminal-A breast cancers (Kim et al., 2014). Breast cancer patients whose tumors express high levels of mitochondrial glycine pathway components have worse prognosis than those with low expression levels (Jain et al., 2012), specifically expression of PHGDH and SHMT (Noh et al., 2014). Across multiple subtypes, high PHGDH and PSPH with low SHMT correlates with short overall survival, and high PSPH and low glycine dehydrogenase (GLDC) with short progression-free survival (Kim et al., 2014). From these and other studies, PHGDH, phosphoserine aminotransferase (PSAT), PSPH, and SHMT may all be useful biomarkers for determining breast cancer prognosis (Antonov et al., 2014; Kim et al., 2014). Copy number increases of the PHGDH gene lead to a 70% increase in PHGDH protein levels in ER-negative breast cancer, moving products of glucose from glycolysis to production of serine and glycine (Possemato et al., 2011). These elevated levels of PHGDH most closely correlate with TNBC and basal-like breast cancer (Locasale et al., 2011; Noh et al., 2014). Suppression of PDGDH expression decreases cell proliferation by lowering production of alpha-ketoglutarate, as serine contributes up to 50% of glutamate flux into the TCA cycle in PHGDH-overexpressing cells (Possemato et al., 2011). Overexpression of PHGDH in MCF-10A breast cells also leads to increased proliferation and anchorage-independent growth, indicating a critical role in transformation (Locasale et al., 2011). Coupled with the knowledge that non-tumorigenic epithelial cells do not require PHGDH for growth (Locasale et al., 2011), suggests that PHGDH is an attractive therapeutic target and biomarker (Amelio et al., 2014). PHGDH contains many KU-0060648 for which specific inhibitors could be designed, and nonspecific inhibitors are already available (Locasale and Cantley, 2011). However, PHGDH deficiencies in children lead to neurological defects, so agents would need to be developed with limited access to the central nervous system, and with therapeutic windows carefully calculated (DeBerardinis, 2011). Serine and glycine metabolism contains many nodes of regulation that can be modulated to decrease the proliferation of breast cancer cells. Especially promising are limiting the intake of serine to deplete nucleotide pools and slow proliferation, and targeting PHGDH and SHMT (Amelio et al., 2014). PHGDH also has potential value as a biomarker for breast cancer staging and prognosis, as well as for predicting response to targeted serine metabolism therapies (Amelio et al., 2014).
    Cysteine metabolism It has long been known that many tumor cells, including some breast cancer cell lines, cannot survive when methionine is replaced by homocysteine, while non-malignant cells survive. Targeting methionine metabolism to combat cancer is has been explored in some detail, and is reviewed elsewhere (Hoffman, 2015). However, prolonged methionine restriction can result in toxic side effects, so treatment options other than dietary restriction and methioninase treatment have gained attention (Cellarier et al., 2003). One such option is targeting cysteine metabolism, as it is involved in methionine metabolism (Fig. 1) but unlike methionine, cysteine itself is not an essential amino acid. Alterations in cysteine levels have been observed in breast cancer, but have not been studied as extensively as glutamine or serine for their potential as biomarkers for different subtypes and staging of breast cancer. Implantation of human breast cancer cells into mice leads to an increase in plasma cysteine and homocysteine as the tumor progresses, indicating that cysteine may have potential as a marker for disease progression (Al-Awadi et al., 2008). Specifically, in PIK3CA-mutant breast cancer cells, cysteine levels increase by 13%. Coupled with the concomitant increase in glutamine, this could account for the observed increase in glutathione levels and allow cells to survive in the presence of elevated levels of reactive oxygen species (ROS) (Kim et al., 2015).