Abstract 3801: Serine starvation inhibits SRSF protein expression and modulates RNA splicing in breast cancer cells

Breast cancer is the most common cancer in women worldwide, and luminal/estrogen receptor positive (ER+) breast cancer accounts for ∼50% of breast cancer deaths. Our lab has identified serine auxotrophy as a metabolic vulnerability of luminal/ER+ breast tumors due to low levels of the serine synthesis enzyme phosphoserine aminotransferase 1 (PSAT1). Serine is critically important for cancer cell growth due to its multiple downstream functions in protein, nucleotide, and lipid biosynthesis. There is considerable interest in starving serine auxotrophic tumors of serine for therapy, including an ongoing clinical trial in pancreatic cancer. While the metabolic effects of serine starvation have been extensively investigated, our goal is to better understand how serine starvation affects protein synthesis and expression. We found that serine starvation inhibits global translation, while inducing adaptive translation of ATF4, and causes ribosome stalling and fall-off at serine TCC codons. Analysis of changes in the proteome upon serine starvation in auxotrophic luminal breast cancer cells shows that serine-rich proteins are particularly sensitive to serine starvation; this includes the serine/arginine-rich splicing factor (SRSF) family that are important regulators of mRNA splicing. Accordingly, replicate multivariate analysis of transcript splicing (rMATS) on RNA-sequencing data suggests that serine starvation dramatically changes alternative mRNA splicing in multiple breast cancer cell lines, with many differential splicing events being conserved across cell lines. These results have led to our current hypothesis that serine starvation induces splicing changes due to reduced translation of serine-rich members of the SRSF family (such as SRSF6), which ultimately impacts DNA damage and cell survival. We believe that SRSF6 depletion and subsequent alteration of RNA splicing upon serine starvation may sensitize to DNA damaging agents (e.g., chemotherapy). Citation Format: Philippa Burns, Negar Tabatabaei, Laura Selfors, Aanshi Vashi, Debolanle O. Dahunsi, Patrick Murphy, Soroush Tahmasebi, Jonathan Coloff. Serine starvation inhibits SRSF protein expression and modulates RNA splicing in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3801.