A novel triaptosis-related prognostic signature to assess the clinical value in HER2-low breast cancer: evidence from clinical cohorts and experimental validation.

[BACKGROUND] HER2-low breast cancer (BC) represents a biologically distinct subtype with limited predictive biomarkers. Triaptosis is a recently described form of oxidative stress-associated endosomal dysfunction mediated by VPS34 inhibition. Although direct execution of triaptotic cell death in human tumors remains unproven, genes related to this pathway may reflect a broader biological context involving endosomal regulation, redox balance, and PI3K signaling.

[METHODS] Gene expression matrix, molecular and clinical characterization were obtained from The Cancer Genome Atlas and cBioPortal. Consensus cluster and lasso regression analyses were used to construct triaptosis-related signature. And multiple center cohorts include Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS) cohorts to validate accuracy and stability of signature. Subsequently, immune correlation, clinical correlation assessment and drug-target interactions were conducted. Finally, key signature genes were validated using functional assays and RNA sequencing and pathway enrichment were employed to elucidate underlying molecular mechanisms.

[RESULTS] Most triaptosis-related genes (TRGs) had different expression levels and mutations in HER2-low BC. A novel signature composed of LRP6, EMB, PYDC1, CEACAM6, and AGR3 was constructed and all multiple center cohorts achieved excellent predictive efficacy. Prognostic value, immune level and drug response were excellent differentiators between risk groups. Finally, functional assays demonstrated that PYDC1 significantly inhibited the proliferation and migration of HER2-low BC cell and pathway analysis indicated that PYDC1 suppressed the proliferation and migration of HER2-low BC cell by attenuating PI3K/AKT signaling.

[CONCLUSION] We developed a prognostic signature based on triaptosis-related genes (TRGs) that robustly stratifies HER2-low BC patients. Our findings support the clinical relevance of TRGs as biomarkers rather than direct evidence of triaptotic cell death, and identify PYDC1 as a functionally relevant suppressor of PI3K/AKT signaling in HER2-low BC.