2. Academic Validation
  3. TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression

TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression

  • Nat Commun. 2023 Apr 24;14(1):2342. doi: 10.1038/s41467-023-38115-2.
Jing Bi # 1,  Zhihui Wu # 1,  Xin Zhang # 1 2,  Taoling Zeng # 1,  Wanjun Dai 1,  Ningyuan Qiu 1,  Mingfeng Xu 1,  Yikai Qiao 1,  Lang Ke 1,  Jiayi Zhao 1,  Xinyu Cao 1,  Qi Lin 1,  Xiao Lei Chen 3 4,  Liping Xie 4,  Zhong Ouyang 5,  Jujiang Guo 6,  Liangkai Zheng 6,  Chao Ma 7,  Shiying Guo 8,  Kangmei Chen 9,  Wei Mo 1,  Guo Fu 10 11 12,  Tong-Jin Zhao 13,  Hong-Rui Wang 14 15
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China.
  • 2 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China.
  • 3 Cancer Research Center of Xiamen University, 361102, Xiamen, Fujian, China.
  • 4 School of Medicine, Xiamen University, 361102, Fujian, China.
  • 5 Department of Breast Surgery, The First Affiliated Hospital of Xiamen University, 361003, Xiamen, Fujian, China.
  • 6 Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, 361003, Xiamen, Fujian, China.
  • 7 Medical School of Chinese PLA, 100853, Beijing, China.
  • 8 GemPharmatech Co., Ltd., 210000, Nanjing, Jiangsu, China.
  • 9 Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China.
  • 10 Cancer Research Center of Xiamen University, 361102, Xiamen, Fujian, China. guofu@xmu.edu.cn.
  • 11 School of Medicine, Xiamen University, 361102, Fujian, China. guofu@xmu.edu.cn.
  • 12 Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, 361003, Xiamen, Fujian, China. guofu@xmu.edu.cn.
  • 13 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, 200438, Shanghai, China. zhaotj@fudan.edu.cn.
  • 14 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China. wanghr@xmu.edu.cn.
  • 15 Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, 361003, Xiamen, Fujian, China. wanghr@xmu.edu.cn.
  • # Contributed equally.
PMID: 37095176 DOI: 10.1038/s41467-023-38115-2
Abstract

Triple-negative breast Cancer (TNBC) is a subtype of breast Cancer with poor outcome and lacks of approved targeted therapy. Overexpression of epidermal growth factor receptor (EGFR) is found in more than 50% TNBC and is suggested as a driving force in progression of TNBC; however, targeting EGFR using Antibodies to prevent its dimerization and activation shows no significant benefits for TNBC patients. Here we report that EGFR monomer may activate signal transducer activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25, whose expression is frequently decreased in human TNBC. Deficiency of TMEM25 allows EGFR monomer to phosphorylate STAT3 independent of ligand binding, and thus enhances basal STAT3 activation to promote TNBC progression in female mice. Moreover, supplying TMEM25 by adeno-associated virus strongly suppresses STAT3 activation and TNBC progression. Hence, our study reveals a role of monomeric-EGFR/STAT3 signaling pathway in TNBC progression and points out a potential targeted therapy for TNBC.

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