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  3. Tyrosine hydroxylase as a therapeutic target: insights from adrenergic nerve and TNBC cell interactions

Tyrosine hydroxylase as a therapeutic target: insights from adrenergic nerve and TNBC cell interactions

  • J Mol Med (Berl). 2026 Mar 19;104(1):53. doi: 10.1007/s00109-026-02657-x.
Yichen Luo # 1 2,  Yanhong Han # 3,  Huilong Nie # 4,  Minghao Feng # 5,  Cuiting Wei 4,  Xiuling Ma 6,  Kefeng Li 6,  Zhuangzhuang Zhang 2,  Guangxue Wang 7,  Wenjun Pan 2,  Xueyang Li 2,  Liutong Yi 1,  De-Yun Wang 8,  Xian-Tao Zeng 9,  Yongkang Qiao 10,  Yan Yan 11,  Yujing Lin 12
Affiliations

Affiliations

  • 1 Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China.
  • 2 Guangdong Provincial Engineering Research Center of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China.
  • 3 Center for Biological Science and Technology, Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, Guangdong, China.
  • 4 Department of Obstetrics and Gynecology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China.
  • 5 Department of Thoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
  • 6 Faculty of Applied Sciences, Macao Polytechnic University, Macau SAR, 999078, China.
  • 7 Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
  • 8 Department of Otolaryngology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, 119228, Singapore.
  • 9 Center for Evidence‑Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 10 Center for Biological Science and Technology, Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, Guangdong, China. [email protected].
  • 11 Guangdong Provincial Engineering Research Center of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China. [email protected].
  • 12 Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China. [email protected].
  • # Contributed equally.
PMID: 41857421 DOI: 10.1007/s00109-026-02657-x
Abstract

The sympathetic adrenergic nerves (SAN) play a significant role in the malignant transformation of breast Cancer cells through the activity of norepinephrine (NE). However, the role of Tyrosine Hydroxylase (TH), a key enzyme of the NE synthesis, in the interaction between the SAN and triple-negative breast Cancer (TNBC) cells has not been sufficiently explored, and whether TH can be a therapeutic target for TNBC has not been reported. TH expression in TNBC was examined by analyzing data from an online database and immunohistochemical analysis of our clinical samples. Cell proliferation and drug sensitivity were assessed upon coculture with fluorescently labeled cells using IncuCyte. Changes in the expression of DNA damage and apoptosis-associated proteins were assessed by western blotting. TH expression and NE synthesis in PC12 cells after their coculture with TNBC cells were measured by RT-qPCR, immunofluorescence, and ELISA. RNA Sequencing was conducted on the cells before and after coculture. TH expression was relatively high in TNBC tumor tissues and closely associated with prognosis. SAN promoted TNBC cell proliferation through NE and reduced TNBC cell sensitivity to chemotherapeutic agents. Additionally, tumor cells induced TH expression in PC12 cells through nerve growth factor (NGF) secretion. Knocking down TH and using TH inhibitors effectively reversed the proliferation-promoting and drug sensitivity-reducing effects of SAN in TNBC cells. TH may be a central molecule in the positive feedback loop between TNBC cells and SAN. TH is a potential prognostic biomarker and can also serve as a therapeutic target for TNBC. KEY MESSAGES: The overexpression of the sympathetic nerve biomarker Tyrosine Hydroxylase (TH) in triple-negative breast Cancer (TNBC) is an indicator for clinical staging, prognosis, and targeted therapy. There is a feedback loop where TH in nerves produces NE, worsening TNBC and reducing chemotherapy effectiveness. TNBC cell then increases TH expression, further boosting NE production. Furthermore, blocking the activity of TH could effectively inhibit this phenotype.

Keywords

3D mammosphere; Chemotherapy sensitivity; Neural-tumor coculture model; Norepinephrine; Triple-negative breast cancer (TNBC); Tyrosine hydroxylase.

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