Lineage-Specific Silencing ofPSAT1Induces Serine Auxotrophy and Sensitivity to Dietary Serine Starvation in Luminal Breast Tumors

SUMMARY A major challenge of targeting metabolism for cancer therapy is pathway redundancy, where multiple sources of critical nutrients can limit the effectiveness of some metabolism-targeted therapies. Here, we analyzed lineage-dependent gene expression in human breast tumors to identify differences in metabolic gene expression that may limit pathway redundancy and create therapeutic vulnerabilities. We found that the serine synthesis pathway gene PSAT1 is the most depleted metabolic gene in luminal breast tumors relative to basal tumors. Low PSAT1 prevents de novo serine biosynthesis and sensitizes luminal breast cancer cells to serine and glycine starvation in vitro and in vivo . This PSAT1 expression disparity—which pre-exists in the putative cells-of-origin of basal and luminal tumors—is due to luminal-specific hypermethylation of the PSAT1 gene. Together, our data demonstrates that luminal breast tumors are auxotrophic for serine and may be uniquely sensitive to dietary serine starvation.