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bioRxiv · 10.1101/2025.06.02.657315

Association of GADD45A and favorable outcome in hormone positive breast cancer

Lin, C.-Y.·Liu, C.-Y.·Chao, T.-C.·Huang, C.-C.·Tsai, Y.-F.·Tseng, L.-M.·Lai, J.-I.
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Abstract

BackgroundHormone receptor-positive (HR(+)) breast cancer is the most prevalent subtype in breast cancer, and although treatment options are rapidly increasing, still poses as an unmet need in advanced cases. Growth arrest and DNA damage-inducible alpha (GADD45A) is a gene with known relationship with the cell cycle and DNA damage pathways. Conflicting roles in breast cancer biology have been reported for GADD45A. In our study, we investigate the clinical and molecular association of GADD45A in HR(+) breast cancer, evaluating its prognostic potential and relationship with estrogen signaling. MethodsGADD45A expression was assessed in 100 breast cancer tissue samples from a tissue microarray and correlated with clinicopathologic parameters. Public genomic datasets were analyzed to validate associations between GADD45A expression and clinical outcomes in HR(+)HER2(-) breast cancer. Gene set enrichment analysis (GSEA) was used to investigate pathway correlations. ResultsGADD45A protein levels were highest in HR(+)HER2(-) tumors and positively correlated with estrogen receptor (ER) levels, consistent with a luminal phenotype. No significant association was observed between GADD45A levels and progression-free survival in CDK4/6 inhibitor-treated patients, suggesting limited predictive utility in this context. However, higher GADD45A expression was significantly associated with improved overall and relapse-free survival in HR(+)HER2(-) breast cancer in the METABRIC cohort, but not in HER2(+) or triple- negative subtypes. GSEA revealed a positive association between GADD45A expression and the estrogen late response signature, suggesting a functional link with hormone signaling. ConclusionGADD45A expression is enriched in luminal-type HR(+) breast cancer and correlates with favorable clinical outcomes. While not predictive of CDK4/6 inhibitor response, GADD45A may serve as a surrogate marker of estrogen signaling and improved prognosis. These findings support further investigation into GADD45A as a biomarker for stratification and potentially as a therapeutic target in HR(+) breast cancer.

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Lin, C.-Y., Liu, C.-Y., Chao, T.-C., Huang, C.-C., Tsai, Y.-F., Tseng, L.-M., Lai, J.-I.. 2025-06-05. Association of GADD45A and favorable outcome in hormone positive breast cancer. https://doi.org/10.1101/2025.06.02.657315

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