Navigating luminal heterogeneity: etiology-based proteogenomic subtyping for targeted treatment strategies in breast cancer

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BACKGROUND: Luminal breast cancer is rising rapidly among East Asian women, particularly younger patients, with variable clinical outcome, yet current risk-stratification models inadequately predict early recurrence of under-studied young-onset cases. We hypothesize that the interplay between endogenous mutagenic processes and overlooked environmental carcinogen exposure drives molecular diversity, revealing novel etiologic and therapeutic insights. METHODS: We performed integrative proteogenomic profiling of 164 prospective, treatment-naïve early-stage Taiwanese breast cancer patients using whole-exome sequencing, transcriptomics, proteomics, and phosphoproteomics. Functional validation in luminal models confirmed therapeutic vulnerabilities and biomarkers, with an independent cohort (n = 270) used to stratify high-risk recurrence patients. RESULTS: Our integrative proteogenomic analysis revealed distinct molecular etiologies and actionable vulnerabilities. For the first time, mutation signature analysis revealed both environmental carcinogen exposure (DBAC) and endogenous APOBEC mutagenesis as key contributors to poor disease-free survival, particularly in younger patients. A high-mutation-burden, immune-evasive subgroup revealed immunoepigenetic vulnerabilities. DBAC-driven tumors exhibited overexpression of ROS-detoxifying enzymes, DNA-damage checkpoint activation, and suppressed DNA repair pathways, supporting an environmental-genomic cooperative mechanism. APOBEC-associated tumors exhibited upregulation of APOBEC3B/3F/3G, steroid hormone biosynthesis enzymes, and downstream oncogenic signaling, forming an immunotherapy-responsive subtype. Proteomic classification further resolved luminal heterogeneity beyond PAM50, identifying two clinically relevant groups: (1) a young DBAC-proteome subset with suppressed DNA-repair machinery and favorable chemotherapy response; and (2) a recurrence-prone subtype characterized by co-activating ER, PI3K-AKT-mTOR, and CDK4/6/9 signaling. Functional validation demonstrated that selective CDK9 inhibition targeting the p-POLR2A-Ser2 axis significantly outperformed CDK4/6 blockade. Furthermore, a companion panel (HDAC2, ALDH1L2, ARF4, SCAMP3) stratified high-risk recurrence patients in an independent cohort, supporting biomarker-guided therapy for aggressive luminal breast cancer. CONCLUSIONS: This study uncovers environmental mutagenesis as a previously overlooked but critical driver of luminal breast cancer heterogeneity in East Asian patients. We establish a proteogenomics-transformative scheme to guide risk stratification and subtype-specific vulnerabilities, offering a precision oncology strategy for early-stage East Asian breast cancer management.

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