The specific mechanisms underlying glutamine dependency are

The specific mechanisms underlying glutamine dependency are still being explored, and current research indicates that the mechanisms likely vary between breast cancer subtypes. In HER2-positive breast cancer, increased levels of the transcriptional activator PGC-1α lead to expression of genes that modulate glutamine metabolism, including GLS and GLUD1, and expression of these genes correlates with poor prognosis. However, this pattern does not hold across other breast cancer subtypes, and therefore other mechanisms must also contribute (McGuirk et al., 2013). Glutamine metabolism also affects the response of Schindler list to chemotherapy. In aromatase inhibitor (AI)-resistant breast cancer, crosstalk between HER2 and ER upregulates glutamine metabolism via c-Myc. c-Myc elevation and glutamine metabolism increases the sensitivity of AI-resistant cells to inhibitors of GLS and the glutamine transporter SLC1A5, and to the removal of external glutamine (Chen et al., 2015; Shajahan-Haq et al., 2014). Glutamine may also play a role in response to paclitaxel. One mechanism by which paclitaxel promotes autophagy and cell death is inducing stress that leads to ubiquitin-mediated degradation of the glutamine transporters SLC1A5 and SLC38A2. This in turn decreases activity of the mechanistic target of rapamycin complex 1 (mTORC1), leading to increased autophagy. Inhibitors of SLC1A5 lead to similar effects in TNBC, thereby reducing glutamine uptake, mTORC1 signaling, and cell growth (van Geldermalsen et al., 2015). Moreover, SLC1A5/38A2 expression may also have promise as a subtype-specific biomarker, as its expression has been correlated with improved prognosis in luminal breast cancer (Jeon et al., 2015), while low expression correlates with increased survival of TNBC in xenograft experiments (van Geldermalsen et al., 2015). While it has long been acknowledged that glutamine metabolism could be a therapeutic target, many early glutamine therapies presented significant toxicity or were ineffective in vivo. More recently, specific GLS inhibitors have been developed and are in clinical trials (Budczies et al., 2015). A study of metabotropic glutamate receptor expression in TNBC indicates that inhibition of receptor-decreased proliferation, and drugs such as Riluzole – already approved for treatment of amyotrophic lateral sclerosis – reduces tumor volume of mouse xenografts by up to 80% (Speyer et al., 2012). A greater understanding of the mechanisms by which glutamine and glutamate sustain cancer cells may lead to the development or repurposing of other successful targeted metabolic therapies and use of the pathway enzymes and metabolites as biomarkers.
Serine and glycine metabolism Serine and glycine are synthesized from the glycolysis intermediate 3-phosphoglycerate by a series of enzymatic reactions (Fig. 1). The methyl groups of glycine can feed one-carbon metabolism in the folate cycle, which is utilized by cancer cells for the synthesis of proteins, nucleic acids, lipids, and cofactors (Amelio et al., 2014; Locasale, 2013). Serine and glycine are also involved in the synthesis of antioxidants, which increase the survival of cancer cells in hypoxic environments (Amelio et al., 2014). Glutamate is also a product of serine synthesis, and its conversion of alpha-ketoglutarate can feed energy production by the TCA cycle (Amelio et al., 2014). Removal of serine and glycine leads to reduced proliferation of breast cancer cells, an effect that can be completely rescued by re-addition of serine but only partially by glycine. Many cancer cells preferentially take up serine over glycine, and when serine is lacking convert glycine into serine, consuming one-carbon units and depleting nucleotide pools (Labuschagne et al., 2014). This indicates a specific role for serine in supporting breast cancer proliferation by a mechanism other than one-carbon metabolism, and this remains to be explored. Additionally, certain breast cancer cell lines exhibit robust growth inhibition in the absence of serine, indicating that serine starvation may be a successful metabolic therapy in specific cases (Labuschagne et al., 2014). Classification of the differences between breast cancer cells that exhibit decreased proliferation in comparison to those that cannot proliferate at all in the absence of serine could reveal potential biomarkers for response to serine deprivation as a therapeutic approach.