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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE323399 | GEO | 2026/03/09

REPOSITORIES: GEO

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Project description:Dysregulated lipid metabolism promotes the progression of various cancers, including breast cancer. This study aimed to explore the lipidomic profiles of breast cancer patients, providing insights into the correlation between lipid compositions and tumor subtypes characterized by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Briefly, 30 breast cancer patients were categorized into four cohorts based on their HR and HER2 status: HR+, HER2 zero (HR+ HER2-0); HR+, HER2 low (HR+ HER2-low); HR+, HER2 pos (HR+ HER2-pos); and HR-, HER2 positive (HR- HER2-pos). Lipidomic profiles were analyzed using high-throughput liquid chromatography-mass spectrometry (LC-MS). Data were processed through principal component analysis (PCA), Partial Least Squares Discriminant Analysis (PLS-DA), and Random Forest (RF) classification to assess lipidomic variations and significant lipid features among these groups. Profiles of lipids, particularly triglycerides (TG) such as TG (16:0_18:1_18:1) +NH4, were significantly different across the cohorts. PCA and PLS-DA analyses identified unique lipid profiles in the HR+ HER2-pos and HR+ HER2-0 groups, while RF highlighted PIP3(21:2)+NH4 as a crucial lipid feature for accurate patient grouping. Advanced statistical analysis showed significant correlations between lipid carbon chain length and the number of double bonds with the classifications, providing insights into the role of structural lipid properties in tumor biology. Additionally, a clustering heatmap and network analysis indicated significant lipid-lipid interactions. Pathway enrichment analysis showed critical biological pathways, such as the assembly of active LPL and LIPC lipase complexes. In conclusion, the study underscores the importance of lipidomic profiling is crucial in understanding the metabolic alterations associated with different breast cancer subtypes. These findings highlight specific lipid features and interactions that may serve as potential biomarkers for breast cancer classification and target pathways for therapeutic intervention. Furthermore, advanced lipidomic analyses can be integrated to decipher complex biological data, offering a foundation for further research into the role of lipid metabolism in cancer progression.

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

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