@article{Zhao2026, 
author = {Yaxin Zhao and Han Wang and Ying Wang and Yizhou Jiang and Xin Hu and Zhiming Shao},
title = {Integrative multi-omic analysis identified ERBB2 mutations and senescence-driven immune suppression as dual therapeutic targets in LAR triple-negative breast cancer},
year = {2026},
journal = {Cancer Biology & Medicine},
volume = {23},
number = {3},
pages = {374-391},
keywords = {Triple-negative breast cancer, cellular senescence, immunotherapy resistance, luminal androgen receptor subtype, ERBB2 mutation},
url = {https://www.sciopen.com/article/10.20892/j.issn.2095-3941.2025.0691},
doi = {10.20892/j.issn.2095-3941.2025.0691},
abstract = {ObjectiveThe luminal androgen receptor (LAR) subtype of triple-negative breast cancer (TNBC) differentiation displays low proliferation yet strong metastatic potential and a poor chemotherapy response. This study aimed to define the molecular basis of the LAR subtype and identify actionable therapeutic targets.MethodsComprehensive multi-omic analyses were performed on the FUSCC-TNBC cohort, integrating whole-exome sequencing, RNA sequencing, and functional validation in vitro and in vivo. Somatic mutation profiling, gene set enrichment analysis (GSEA), and weighted gene co-expression network analysis (WGCNA) were used to define genomic and transcriptomic signatures. A machine learning model using the Mime1 package was applied to derive a senescence-associated prognostic signature (LAR-S) and validation in external cohorts. Immune deconvolution was performed to decipher the tumor microenvironment. Functional assays, patient-derived organoids (PDOs), and TS/V mouse models were used to evaluate therapeutic responses to senescence-modulating agent and immunotherapy combinations.ResultsThe LAR subtype was enriched for PIK3CA, PTEN, and ERBB2 kinase domain mutations. Functional studies confirmed ERBB2 variants (e.g., V777L and E698_P699delinsA) as oncogenic drivers conferring sensitivity to neratinib. Transcriptomic analyses revealed a dominant cellular senescence program associated with immune suppression. The LAR-S signature stratified survival across cohorts and predicted immunotherapy resistance. Targeting cellular senescence inhibited LAR subtype organoid growth and when combined with anti-PD-1 therapy synergistically suppressed tumor growth in vivo.ConclusionsThe LAR subtype harbors two therapeutic vulnerabilities: ERBB2 mutation-driven kinase activation; and senescence-mediated immune evasion. The LAR-S signature enables precise patient stratification and supports senescence-targeted and immunotherapy combination strategies as promising approaches for this refractory TNBC subtype.}
}