Evidence map›Paper›PMID 42237381›Full record

ArticleMolecular cancer2026

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

Ya-Hsuan Chang, Yi-Ju Chen, Zhi-Jie Hong, Yi-Jing Hsiao, Kuen-Tyng Lin, Guo-Shiou Liao, Sheng-Fang Su, Ze-Shiang Lin, Huei-Wen Chen, Chia-Li Han and 30 more

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Article in Molecular cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

40 authors.

Ya-Hsuan Chang *Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
Yi-Ju Chen *Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Zhi-Jie Hong *Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
Yi-Jing Hsiao *Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Kuen-Tyng Lin *Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Guo-Shiou Liao *Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
Sheng-Fang Su *Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
Ze-Shiang Lin *Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Huei-Wen Chen *Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan.
Chia-Li Han *Master Program in Clinical Genomics and Proteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Eric Sheng-Wen ChenInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Yin-Chen HsuDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Yan-Ming ChenDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Hao FangInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Hao-Chin YangInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Yan-Si ChenInstitute of Statistical Science, Academia Sinica, Taipei, Taiwan.
Chien-Yu LinInstitute of Statistical Science, Academia Sinica, Taipei, Taiwan.
Hsiang-En HsuInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Ching-Hung LinDepartment of Medical Oncology, Cancer Center Branch, National Taiwan University Hospital, Taipei, Taiwan.
Pin-Lian JiangInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Pei-Shan WuInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Ching-Wen ChenInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Chen-Ting HungInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Ethan WuInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Wei-Tzu ChiuInstitute of Chemistry, Academia Sinica, Taipei, Taiwan.
Fan-Ni HsingDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Tsai-Pei LiuDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chia-Yu WangDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Yu-Tai WangNational Center for High-performance Computing, National Institutes of Applied Research, Hsinchu, Taiwan.
Chang-Wei YehNational Center for High-performance Computing, National Institutes of Applied Research, Hsinchu, Taiwan.
Ki-Hok LiaoNational Center for High-performance Computing, National Institutes of Applied Research, Hsinchu, Taiwan.
Ana I RoblesOffice of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
Henry RodriguezOffice of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
Show-Ling YangInstitute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Mien-Chie HungGraduate Institute of Biomedical Sciences, Cancer Biology and Precision Therapeutics Center, Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
Yen-Shen LuDepartment of Oncology, National Taiwan University Hospital, Taipei, Taiwan. yslu@ntu.edu.tw.
Hsuan-Yu ChenInstitute of Statistical Science, Academia Sinica, Taipei, Taiwan. hychen@stat.sinica.edu.tw.
Sung-Liang YuDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. slyu@ntu.edu.tw.
Jyh-Cherng YuDepartment of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan. doc20106@ndmctsgh.edu.tw.
Yu-Ju ChenInstitute of Chemistry, Academia Sinica, Taipei, Taiwan. yujuchen@as.edu.tw.

Funding

Academia Sinica Common Mass Spectrometry Facilities AS-CFII-111-209Intelligent Multi-Omics Precision Medicine AS-KPQ-115-IMPMKey and Novel Therapeutics Development Program for Major Diseases AS-KPQ-111-KNTMedicinal Chemistry and Analytical Core Facilities AS-NBRPCF-111-201National Center for High-performance Computing (NCHC) of National Institutes of Applied Research (NIAR) and National Core Facility for Biopharmaceuticals NCFB 111-2740-B-492-001; NCFB, NSTC 114-2740-B-492-001National Core Facility for Biopharmaceuticals Pharmacogenomics Lab TR6 MOST 111-2740-B-002-005Next-Generation Pathway of Taiwan Cancer Precision Medicine Program AS-KPQ-107-TCPMPTri-Service General Hospital MOST 105-2314-B-016-041-MY3, MOST 107-2314-B-016-025, and TSGH-C108-126
6 · The paper itself

Abstract

backgroundLuminal 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.

methodsWe 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.

resultsOur 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.

conclusionsThis 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.

Indexed as

Biomarkers, TumorBreast NeoplasmsProteogenomicsExome SequencingFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticHumansMolecular Targeted TherapyMutationPrognosisProteomicsBiomarkers, TumorAPOBECBreast cancerCarcinogenCDK9Luminal subtypeProteogenomics

Identifiers

PMID42237381
PMCPMC13459638

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