Abstract 1779: De novo purine pathway enzyme ATIC promotes tumor progression and modulates metabolic reprogramming in breast cancer

Abstract Breast cancer (BC), a complex and heterogeneous disease, poses a significant global health challenge with a pressing need for enhanced prognostic markers and therapeutic targets. This study focuses on 5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), an enzyme essential in de novo purine biosynthesis and previously implicated in myeloma and hepatocellular carcinoma progression. Leveraging publicly available datasets, including TCGA, METABRIC, and GENT2, we identified elevated ATIC expression in BC tissues compared to normal tissues. Notably, patients with elevated ATIC expression displayed significantly diminished overall survival rates, underscoring ATIC's potential as a prognostic marker. Functional assays involving ATIC downregulation in BC cell lines revealed suppressed cell growth, migration, and increased sensitivity to chemotherapeutic drug, Doxorubicin, implicating ATIC in BC progression. Further, RNA-sequencing analysis of ATIC knockdown (KD) BC cell lines revealed a positive correlation between ATIC expression and the activation of MYC and E2F-regulated pathways. The marked attenuation in cell growth and various tumor properties upon ATIC KD provides mechanistic insights into the role of ATIC in fueling BC progression, potentially through the modulation of MYC and E2F target gene expression. Gene Set Enrichment Analysis (GSEA) on differentially expressed genes identified between tumors with high ATIC expression and low ATIC expression in BC patients from the TCGA cohort revealed a notable enrichment of genes associated with MYC and E2F targets, providing additional support for the observed molecular associations in our experimental model. Intriguingly, ATIC KD in Triple Negative BC cell line unexpectedly led to an increase in fatty acid β-oxidation (FAO), uncovering a metabolic vulnerability in these cells. In conclusion, this study unravels the multifaceted role of ATIC in BC, demonstrating its influence on BC tumor progression and metabolism. The observed increase in FAO upon ATIC KD presents a novel metabolic vulnerability that could be explored for targeted therapeutic interventions in BC. This comprehensive analysis contributes valuable insights toward understanding ATIC as a potential therapeutic target and prognostic indicator in BC. Citation Format: Divya Murthy, Kuldeep S. Attri, Jun Hyoung Park, Benny A. Kaipparettu. De novo purine pathway enzyme ATIC promotes tumor progression and modulates metabolic reprogramming in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1779.