2. Academic Validation
  3. Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis and radiotherapy resistance through JNK pathway

Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis and radiotherapy resistance through JNK pathway

  • Breast Cancer Res. 2024 Jan 2;26(1):1. doi: 10.1186/s13058-023-01758-6.
Jinqiu Tao # 1,  Cailin Xue # 2,  Meng Cao # 1,  Jiahui Ye 1,  Yulu Sun 1,  Hao Chen 1,  Yinan Guan 1,  Wenjie Zhang 3,  Weijie Zhang 4,  Yongzhong Yao 5
Affiliations

Affiliations

  • 1 Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
  • 2 Division of Hepatobilliary Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
  • 3 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. drzhangwj@163.com.
  • 4 Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China. zhangweijie1616@nju.edu.cn.
  • 5 Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China. yyz1006@hotmail.com.
  • # Contributed equally.
PMID: 38167446 DOI: 10.1186/s13058-023-01758-6
Abstract

Background: Despite radiotherapy ability to significantly improve treatment outcomes and survival in triple-negative breast Cancer (TNBC) patients, acquired resistance to radiotherapy poses a serious clinical challenge. Protein disulfide isomerase exists in endoplasmic reticulum and plays an important role in promoting protein folding and post-translational modification. However, little is known about the role of protein disulfide isomerase family member 4 (PDIA4) in TNBC, especially in the context of radiotherapy resistance.

Methods: We detected the presence of PDIA4 in TNBC tissues and paracancerous tissues, then examined the proliferation and Apoptosis of TNBC cells with/without radiotherapy. As part of the validation process, xenograft tumor mouse model was used. Mass spectrometry and western blot analysis were used to identify PDIA4-mediated molecular signaling pathway.

Results: Based on paired clinical specimens of TNBC patients, we found that PDIA4 expression was significantly higher in tumor tissues compared to adjacent normal tissues. In vitro, PDIA4 knockdown not only increased Apoptosis of tumor cells with/without radiotherapy, but also decreased the ability of proliferation. In contrast, overexpression of PDIA4 induced the opposite effects on Apoptosis and proliferation. According to Co-IP/MS results, PDIA4 prevented Tax1 binding protein 1 (TAX1BP1) degradation by binding to TAX1BP1, which inhibited c-Jun N-terminal kinase (JNK) activation. Moreover, PDIA4 knockdown suppressed tumor growth xenograft model in vivo, which was accompanied by an increase in Apoptosis and promoted tumor growth inhibition after radiotherapy.

Conclusions: The results of this study indicate that PDIA4 is an oncoprotein that promotes TNBC progression, and targeted therapy may represent a new and effective anti-tumor strategy, especially for patients with radiotherapy resistance.

Keywords

Apoptosis; PDIA4; Radiation resistance; TAXBP1 JNK; TNBC.

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