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  3. MSLN-mediated activation of EGFR-ERK1/2 signaling drives liver metastasis in breast cancer

MSLN-mediated activation of EGFR-ERK1/2 signaling drives liver metastasis in breast cancer

  • Cell Death Discov. 2026 Jan 9;12(1):11. doi: 10.1038/s41420-025-02835-9.
Jing Chen # 1 2,  Zexiu Lu # 1 2,  Guowu Zhang # 3,  Die Meng 2,  Chao Chang 2,  Jian Chen 4,  Boxuan Wang 2,  Yanran Tong 2,  Yuhang Hai 2,  Ming Lei 4,  Xingyu Yang 2,  Yubi Gan 2,  Chaoqun Deng 2,  Peijin Dai 2,  Manran Liu 5 6 7,  Xi Tang 8
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
  • 3 Department of Breast Surgery, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 6 Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China. [email protected].
  • 7 Department of Breast Surgery, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 8 Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 41513618 DOI: 10.1038/s41420-025-02835-9
Abstract

Breast Cancer (BC) is the most prevalent malignant disease affecting female patients globally, with triple-negative breast Cancer (TNBC) being the subtype linked to the poorest clinical outcome. The liver is a frequent metastatic site of breast Cancer. Therefore, elucidating the mechanism underlying liver metastasis in TNBC is crucial for identifying effective diagnostic and therapeutic targets, which holds significant potential for guiding clinical treatment. This study aimed to identify key genes driving breast Cancer liver metastasis and to explore their functional mechanisms. Using RNA Sequencing of metastatic 4T1-HM3 and primary 4T1-Pri tumor cells, Mesothelin (MSLN) was identified as significantly upregulated in metastatic TNBC cells and tissues, as confirmed by qRT-PCR, Western blot, and immunohistochemistry. Further investigations revealed that MSLN overexpression is strongly correlated with liver metastasis compared to metastases at Other sites. Mechanistically, MSLN binds to epidermal growth factor receptor (EGFR) and activates the EGFR-ERK1/2 signaling axis, thereby promoting TNBC cell survival and proliferation during metastasis. Importantly, targeting MSLN with a paclitaxel/carboplatin combination effectively inhibited liver metastasis of hepatotropic TNBC in a mouse model. Therefore, our study elucidates the role of the MSLN-mediated EGFR-ERK1/2 signaling pathway in TNBC liver metastasis and highlights potential targeted therapies for treating TNBC liver metastasis.

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