Abstract PS2-12-16: Tp53 mutant tnbc overexpresses serine biosynthesis genes psat1 and phgdh and may demonstrate vulnerability to dietary glycine supplementation

Abstract INTRODUCTION Treatment of TNBC is limited by a lack of identifiable therapeutic targets. One of the biggest gene expression differences between TNBC and luminal breast cancer is upregulation of serine biosynthesis enzyme PSAT1. PSAT1 (and, from the same pathway, PHGDH) upregulation correlates with TP53 loss-of-function mutations, common in TNBC. PSAT1 upregulation is negatively correlated with luminal breast cancer genes including ESR1, GATA3 and FOXA1. Since serine deplete diets are likely impractical, glycine supplementation may be toxic to serine-dependent TNBC cells through its effect on one-carbon metabolism. A randomized trial of chemotherapy with or without glycine supplementation is warranted. METHODS We used Breast Cancer Gene-Expression Miner v5.2 (Integrated Center for Oncology), muTarget (Semmelweis University) and GEPIA (Peking University) to interrogate publicly available datasets including METABRIC, GTEx, SCAN-B and TCGA. We looked for serine biosynthesis genes and TP53-regulated genes on well characterized gene sets Oncotype DX, PAM50 and Mammaprint. RESULTS PHGDH is one of the PAM50 genes and its upregulation correlates with the TNBC (basal) subset and is inversely related to the luminal subset. Neither serine biosynthesis gene is present on Oncotype DX or Mammaprint. TP53 mutations are associated with upregulation of 10 genes and downregulation of 7 genes on the PAM50 gene set. PSAT1 is expressed 4-5 times higher in TNBC vs. luminal breast cancers (p<0.0001). PSAT1 is upregulated 2.64 times and PHGDH 2.37 times in TP53 mutated vs wildtype breast cancers. ESR1 (5.4 fold), GATA3 (3.33 fold) and FOXA1 gene expression is downregulated in TP53 mutated breast cancers. ESR1, GATA3 and FOXA1 gene expression is inversely correlated with PSAT1 gene expression (correlation coefficient -0.69 to -0.76). ESR1 gene expression is highly correlated with GATA3 (0.84) and FOXA1 (0.75) and inversely correlated with PSAT1 (-0.76). GATA3 mutations correspond to upregulation of GATA3 gene expression (2.45 times), ESR1 (2.39 times) and FOXA1 (1.86 times). GATA3 mutations correspond to downregulation of PSAT1 (1.65 times) and PHGDH (1.68 times). CONCLUSIONS TNBC is frequently characterized by mutations in TP53 and demonstrate upregulation of serine biosynthesis genes PHGDH and PSAT1. Luminal breast cancers harbor TP53 mutations less frequently and demonstrate downregulation of serine biosynthesis genes. At least 17 of the PAM50 genes are differentially regulated by TP53 mutations, including PHGDH. Glycine supplementation may target a particular vulnerability in TP53 mutant TNBCs. Citation Format: J. Cohen. Tp53 mutant tnbc overexpresses serine biosynthesis genes psat1 and phgdh and may demonstrate vulnerability to dietary glycine supplementation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-12-16.