GADD45A links Hippo-TEAD signaling to estrogen response and luminal identity in HR-positive breast cancer

Growth arrest and DNA damage-inducible alpha (GADD45A) has context-dependent roles in cancer, yet its function in hormone receptor-positive (HR+) breast cancer remains poorly defined. We characterized GADD45A across breast cancer subtypes and investigated its prognostic significance and connection to estrogen and Hippo-TEAD signaling in HR+HER2− breast cancer. GADD45A protein expression was evaluated by immunohistochemistry in 100 tissue microarray samples and 16 CDK4/6 inhibitor-treated metastatic cases. Prognostic associations were assessed in the METABRIC (n = 1,904) and TCGA-BRCA cohorts. siRNA-mediated GADD45A knockdown was performed in MCF7 and T47D cells followed by RNA sequencing and integration with TEAD4 ChIP-seq data. GADD45A protein was preferentially expressed in HR+HER2− tumors and correlated with estrogen receptor levels. High GADD45A expression was associated with improved overall and relapse-free survival in HR+HER2− breast cancer but not in other subtypes. GADD45A knockdown led to downregulation of estrogen response and Hippo-TEAD positive effector programs with concurrent upregulation of E2F targets and cell cycle pathways. Integration with TEAD4 ChIP-seq data demonstrated significant enrichment of TEAD4 promoter binding among GADD45A-regulated genes, including Hippo-TEAD components, chromatin remodeling machinery, and luminal identity regulators. GADD45A is a subtype-specific prognostic marker in HR+HER2− breast cancer that sustains estrogen-responsive and TEAD-mediated transcriptional programs, identifying it as a previously unrecognized link between Hippo-TEAD signaling and luminal gene maintenance.