Targeting Serine Auxotrophy in Luminal Breast Cancer

PROJECT SUMMARY/ABSTRACT A major challenge of targeting metabolism for cancer therapy is pathway redundancy, where multiple sources of critical nutrients can diminish the effects of metabolic therapies. An example of this can be found in recent attempts to target the serine synthesis pathway for cancer therapy, where the abundance of serine available to be taken up from the circulation has hampered the success of inhibitors of serine biosynthesis. This places a premium on pursuing strategies of limiting pathway redundancy if we wish to successfully target serine and other critical metabolic pathways for cancer therapy. We have taken the approach of analyzing human tumor gene expression data to identify scenarios where pathway redundancy is limited due to lineage-dependent gene expression, thereby creating potential vulnerabilities. Using this approach, we have found that the two major lineages of breast tumors—luminal and basal—express vastly different levels of PSAT1 (phosphoserine aminotransferase 1), the gene encoding the second enzyme of the serine synthesis pathway. Luminal breast cancer cells, which express extremely low levels of PSAT1, are unable to activate the serine synthesis pathway even when extracellular serine is completely absent. As a result, they are entirely dependent on exogenous serine for proliferation and survival. This is in contrast to basal breast cancer cells, which are able to synthesize serine and proliferate in the absence of extracellular serine. Mechanistically, this serine auxotrophy appears to be due to luminal-specific methylation of the PSAT1 gene. Based on this data, we have developed the hypothesis that lineage-specific epigenetic silencing of the PSAT1 gene induces serine auxotrophy in luminal breast tumors and makes them vulnerable to inhibition of serine uptake. In this proposal, we will 1) determine whether luminal breast tumors are sensitive to dietary serine starvation in vivo, 2) define the mechanism of PSAT1 suppression in luminal tumors, and 3) identify and characterize serine transporters as potential pharmacological targets of this vulnerability. While luminal breast cancer patients initially have a favorable prognosis due to the utility of endocrine therapies, over half of all patients eventually develop resistance to these therapies and undergo relapse. As a result, over half of all breast cancer fatalities are due to luminal breast cancer, making this an area of significant unmet clinical need. The experiments described in this proposal have the potential to identify new therapeutic options for patients with advanced luminal breast cancer.