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Integrin β4 promotes DNA damage drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/Rac1

  1. Huan Fang
  2. Wenlong Ren
  3. Qiuxia Cui
  4. Huichun Liang
  5. Chuanyu Yang
  6. Wenjing Liu
  7. Xinye Wang
  8. Xue Liu
  9. Yujie Shi author has email address
  10. Jing Feng author has email address
  11. Ceshi Chen author has email address
  1. Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences. Kunming, Yunnan, China.
  2. Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, Yunnan, China.
  3. School of Life Science, University of Science & Technology of China. Hefei, Anhui, China.
  4. Affiliated Hospital of Guangdong Medical University. Zhanjiang, Guangdong, China.
  5. Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, China.
  6. Shanghai University of Medicine & Health Sciences, Affiliated Sixth People’s Hospital South Campus, Shanghai, China.
  7. Department of Pathology, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, Henan, 450003, China.
  8. The Second Affiliated Hospital of the Chinese University of Hong Kong (Shenzhen), Shenzhen, 518172, China.
  9. Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China.
  10. The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China.

Editors

  • Reviewing Editor
    Yongliang Yang
    Dalian University of Technology, Dalian, China
  • Senior Editor
    Caigang Liu
    Shengjing Hospital of China Medical University, Shenyang, China

Reviewer #1 (Public Review):

In this study, Fang H et al. describe a potential pathway, ITGB4-TNFAIP2-IQGAP1-Rac1, that may involve in the drug resistance in triple negative breast cancer (TNBC). Mechanistically, it was demonstrated that TNFAIP2 bind with IQGAP1 and ITGB4 activating Rac1 and the following drug resistance. The present study focused on breast cancer cell lines with supporting data from mouse model and patient breast cancer tissues. The study is interesting. The experiments were well controlled and carefully carried out. The conclusion is supported by strong evidence provided in the manuscript. The authors may want to discuss the link between ITGB4 and Rac 1, between IQGAP1 and Rac1, and between TNFAIP2 and Rac1 as compared with the current results obtained. This is important considering some recent publications in this area (Cancer Sci 2021, J Biol Chem 2008, Cancer Res 2023).

Reviewer #2 (Public Review):

Breast cancer is the most common malignant tumor in women. One of subtypes in breast cancer is so called triple-negative breast cancer (TNBC), which represents the most difficult subtype to treat and cure in the clinic. Chemotherapy drugs including epirubicin and cisplatin are widely used for TNBC treatment. However, drug resistance remains as a challenge in the clinic. The authors uncovered a molecular pathway involved in chemotherapy drug resistance, and molecular players in this pathway represent as potential drug targets to overcome drug resistance. The experiments are well designed and the conclusions drawn mostly were supported by the data. The findings have potential to be translated into the clinic.

Reviewer #3 (Public Review):

In this manuscript, Fang and colleagues found that IQGAP1 interacts with TNFAIP2, which activates Rac1 to promote drug resistance in TNBC. Furthermore, they found that ITGB4 could interact with TNFAIP2 to promote TNBC drug resistance via the TNFAIP2/IQGAP1/Rac1 axis by promoting DNA damage repair.

This work has good innovation and high potential clinical significance.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation