2. Academic Validation
  3. Metformin sensitizes triple-negative breast cancer to histone deacetylase inhibitors by targeting FGFR4

Metformin sensitizes triple-negative breast cancer to histone deacetylase inhibitors by targeting FGFR4

  • J Biomed Sci. 2025 Mar 17;32(1):36. doi: 10.1186/s12929-025-01129-7.
Zhangyuan Gu # 1,  Fugui Ye # 2 3,  Hong Luo # 2 3,  Xiaoguang Li 4,  Yue Gong 2 3,  Shiqi Mao 5,  Xiaoqing Jia 1,  Xiangchen Han 2 3,  Boyue Han 2 3,  Yun Fu 1,  Xiaolin Cheng 1,  Jiejing Li 1,  Zhiming Shao 6 7 8,  Peizhen Wen 9 10,  Xin Hu 11 12 13,  Zhigang Zhuang 14
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Shanghai Key Laboratory of Maternal-Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, No. 2699 West Gao-Ke Road, Shanghai, 201204, China.
  • 2 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, No.688 Hong-Qu Road, Shanghai, 200032, China.
  • 3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 4 Shanghai Henlius Biotech Inc., Shanghai, 200233, China.
  • 5 Department of Medical Oncology, Shanghai Pulmonary Hospital, Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China.
  • 6 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, No.688 Hong-Qu Road, Shanghai, 200032, China. zhi_ming_shao@163.com.
  • 7 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. zhi_ming_shao@163.com.
  • 8 Precision Cancer Medical Center, Affiliated to Fudan University Shanghai Cancer Center, No.688 Hong-Qu Road, Shanghai, 201315, China. zhi_ming_shao@163.com.
  • 9 Department of General Surgery, School of Medicine, Organ Transplantation Clinical Medical Center of Xiamen University, Xiang'an Hospital of Xiamen University, Xiamen University, No. 2000 Xiang'an East Road, Xiamen, 361005, Fujian, China. wenpeizhen1996@163.com.
  • 10 Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Organ Transplantation Institute of Xiamen University, Xiamen University, Xiamen, 361005, Fujian, China. wenpeizhen1996@163.com.
  • 11 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, No.688 Hong-Qu Road, Shanghai, 200032, China. xinhu@fudan.edu.cn.
  • 12 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. xinhu@fudan.edu.cn.
  • 13 Precision Cancer Medical Center, Affiliated to Fudan University Shanghai Cancer Center, No.688 Hong-Qu Road, Shanghai, 201315, China. xinhu@fudan.edu.cn.
  • 14 Department of Breast Surgery, Shanghai Key Laboratory of Maternal-Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, No. 2699 West Gao-Ke Road, Shanghai, 201204, China. zhuangzhigang1971@163.com.
  • # Contributed equally.
PMID: 40091020 DOI: 10.1186/s12929-025-01129-7
Abstract

Background: Triple-negative breast Cancer (TNBC) is characterized by high malignancy, strong invasiveness, and a propensity for distant metastasis, leading to poor prognosis and relatively limited treatment options. Metformin, as a first-line oral hypoglycemic agent, has garnered widespread research interest in recent years due to its potential in Cancer prevention and treatment. However, its efficacy varies significantly across different tumor types. Histone deacetylase inhibitors (HDACi), such as SAHA, have demonstrated antitumor activity, but TNBC responds poorly to HDACi monotherapy, possibly due to feedback activation of the JAK-STAT pathway. Exploring the synergistic potential and underlying mechanisms of combining metformin with HDACi in TNBC treatment is crucial.

Methods: We predicted the synergistic effects of metformin and SAHA in TNBC using multiple computational methods (CMap, DTsyn, and DrugComb). We also developed a cancer-specific compound mimic library (CDTSL) and applied a three-step strategy to identify genes fitting the "metformin sensitization" model. Subsequently, we evaluated the synergistic effects of metformin and SAHA in TNBC cell lines through cell proliferation, colony formation, and Apoptosis assays. Furthermore, we investigated the molecular mechanisms of the combined treatment using techniques such as transcriptome Sequencing, chromatin immunoprecipitation (ChIP), Western blotting, and measurement of extracellular acidification rate (ECAR). Additionally, we assessed the in vivo antitumor effects of the combined therapy in a nude mouse subcutaneous xenograft model.

Results: CMap, DTsyn, and DrugComb all predicted the synergistic effects of SAHA and metformin in TNBC. The screening results revealed that HDAC10 played a key role in metformin sensitization. We found that the combination of metformin and SAHA exhibited synergistic antitumor effects (combination index CI < 0.9) in TNBC cell lines. Mechanistically, metformin inhibited histone acetylation on FGFR4, thereby blocking the feedback activation of FGFR4 downstream pathways induced by SAHA. Furthermore, metformin interfered with the glycolysis process induced by SAHA, altering the metabolic reprogramming of tumor cells. In in vivo experiments, the combined treatment of metformin and SAHA significantly inhibited the growth of subcutaneous tumors in nude mice.

Conclusions: Metformin enhances the sensitivity of TNBC to HDAC inhibitors by blocking the FGFR4 pathway and interfering with metabolic reprogramming. When used in combination with SAHA, metformin exhibits synergistic antitumor effects. Our study provides a theoretical basis for the combined application of HDAC inhibitors and metformin, potentially offering a new strategy for the treatment of TNBC.

Keywords

Drug synergism; Histone deacetylase inhibitors; Metformin; Triple-negative breast neoplasms.

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