ATP1A2 as a subtype-associated candidate prognostic biomarker in breast cancer: an integrated transcriptomic, epigenetic and in vitro analysis

Background To evaluate ATP1A2 as a subtype-associated candidate prognostic biomarker in breast cancer by integrating transcriptomic, epigenetic, immune, survival, and in vitro expression analyses.Research design and methods ATP1A2 mRNA expression was analyzed using TCGA-BRCA data from 1,087 patients and compared across clinicopathological and molecular features. DNA methylation was evaluated across twelve ATP1A2 CpG sites, and RT-qPCR was performed in breast cancer cell lines representing luminal, HER2-enriched, and triple-negative models under basal conditions and after therapeutic exposure.Results ATP1A2 expression was reduced in breast tumors compared with tumor-adjacent normal breast tissue and followed a subtype-dependent pattern, with the lowest levels in basal-like tumors and the highest in luminal A and normal-like tumors. Low ATP1A2 expression was associated with aggressive clinicopathological features, hormone receptor negativity, HER2 positivity, and non-luminal subtypes. High ATP1A2 expression predicted improved overall and disease-free survival and remained independently associated with overall survival. Basal-like tumors displayed ATP1A2 amplification despite reduced mRNA expression, suggesting possible passenger-gene behavior within the 1q21-q23 amplicon. Methylation and immune analyses suggested epigenetic and microenvironmental influences, whereas in vitro assays showed treatment-associated transcriptional modulation.Conclusions ATP1A2 s associated with breast cancer subtype and independently predicts overall survival, warranting further independent validation.