Proteogenomic Landscape of Breast Ductal Carcinoma Reveals Tumor Progression Characteristics and Therapeutic Targets

  • Adv Sci (Weinh). 2024 Oct 17:e2401041. doi: 10.1002/advs.202401041.
Ganfei Xu  1 ,  Juan Yu  1 ,  Jiacheng Lyu  1 ,  Mengna Zhan  1 ,  Jie Xu  1 ,  Minjing Huang  1 ,  Rui Zhao  2 ,  Yan Li  1 ,  Jiajun Zhu  1 ,  Jinwen Feng  1 ,  Subei Tan  1 ,  Peng Ran  1 ,  Zhenghua Su  1 ,  Xinhua Liu  1 ,  Jianyuan Zhao  2 ,  Hongwei Zhang  1 ,  Chen Xu  1 ,  Jun Chang  1 ,  Yingyong Hou  1 ,  Chen Ding  1  3
Affiliations
  • 1. State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
  • 2. Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
  • 3. Departments of Cancer Research Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Translational Biomedical Engineering, Urumqi, 830000, P. R. China.
PMID: 39418072 DOI: 10.1002/advs.202401041
Abstract

Multi-omics studies of breast ductal carcinoma (BRDC) have advanced the understanding of the disease's biology and accelerated targeted therapies. However, the temporal order of a series of biological events in the progression of BRDC is still poorly understood. A comprehensive proteogenomic analysis of 224 samples from 168 patients with malignant and benign breast diseases is carried out. Proteogenomic analysis reveals the characteristics of linear multi-step progression of BRDC, such as tumor protein P53 (TP53) mutation-associated Estrogen receptor 1 (ESR1) overexpression is involved in the transition from ductal hyperplasia (DH) to ductal carcinoma in situ (DCIS). 6q21 amplification-associated nuclear receptor subfamily 3 group C member 1 (NR3C1) overexpression helps DCIS_Pure (pure DCIS, no histologic evidence of invasion) cells avoid immune destruction. The T-cell lymphoma invasion and metastasis 1, Androgen Receptor, and aldo-keto reductase family 1 member C1 (TIAM1-AR-AKR1C1) axis promotes cell invasion and migration in DCIS_adjIDC (DCIS regions of invasive cancers). In addition, AKR1C1 is identified as a potential therapeutic target and demonstrated the inhibitory effect of aspirin and dydrogesterone as its inhibitors on tumor cells. The integrative multi-omics analysis helps to understand the progression of BRDC and provides an opportunity to treat BRDC in different stages.

Keywords
AKR1C1; breast ductal carcinoma; progression; proteogenomics; sterol hormone receptor.
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