Phosphoproteome landscape of ARID1A and its implications in DNA damage response and breast cancer pathogenesis.

ARID1A, a subunit of the SWI/SNF chromatin-remodeling complex, plays a critical role in maintaining genomic stability and regulating estrogen receptor (ER) signaling, yet its phosphorylation dynamics in cancer remain underexplored. This study employed phosphoproteomic analysis to investigate ARID1A phosphorylation in breast cancer, identifying predominant phosphosites-S363, S1184, and S696-regulated by kinases such as MAPK14, CDK16, and MAPK9. Functional enrichment revealed ARID1A interactions with SWI/SNF components (e.g., PBRM1, SMARCC2, BRD9) and DNA damage response (DDR) proteins (e.g., TP53BP1, TOP2A, CHEK2, NBN), underscoring its dual role in chromatin remodeling and double-strand break repair. Notably, phosphorylation at S363 and S1184 was significantly upregulated in breast cancer, suggesting tumour-specific hyperphosphorylation that may disrupt ARID1A tumour-suppressive function and contribute to endocrine resistance. Dysregulation of these phosphorylation events correlated with enhanced MAPK signaling, cancer progression, and poor prognosis. These findings position ARID1A as a molecular hub linking chromatin dynamics to genome integrity, with implications for therapeutic resistance. Targeting ARID1A phosphorylation pathways, potentially via MAPK inhibitors or BRD4/BRD9 antagonists, could restore its suppressive activity and improve treatment outcomes in breast cancer. This study enhances our understanding of ARID1A regulatory mechanisms, highlighting its phosphorylation as a key driver of breast cancer biology. Future research should validate these kinase-substrate interactions and explore their transcriptional and chromatin-level impacts to develop precision therapies for ARID1A-dysregulated cancers.