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Carbidopa suppresses estrogen receptor-positive breast cancer via AhR-mediated proteasomal degradation of ERα

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Summary

Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson’s disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.

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Funding

This research was supported by Zhejiang Province Natural Science Foundation (LQ19H300001, LYY21H300007), Wenzhou Municipal Science and Technology Bureau (Y20190174), and Excellent Young Scientist Training Program fund from Wenzhou Medical University.

Author information

Author notes

  1. Zhiwei Chen, Xing Xia and Heyan Chen these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, China

    Zhiwei Chen, Xing Xia, Heyan Chen, Huirong Huang, Xingsi An, Meng Sun, Ruijie Chen, Vadivel Ganapathy & Longfa Kou

  2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju, 61186, Korea

    Zhiwei Chen & Kwonseop Kim

  3. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Zhiwei Chen & Qing Yao

  4. Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, 325027, Zhejiang, China

    Xing Xia, Heyan Chen, Huirong Huang, Xingsi An, Meng Sun, Qing Yao, Hailin Zhang, Maoping Chu, Ruijie Chen, Vadivel Ganapathy & Longfa Kou

  5. Department of Children’s Respiration Disease, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, China

    Hailin Zhang

  6. Pediatric Research Institute, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, China

    Maoping Chu

  7. Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA

    Yangzom D. Bhutia & Vadivel Ganapathy

Authors
  1. Zhiwei Chen
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Contributions

Conceived the study and designed the experiment: Longfa Kou, Maoping Chu, Ruijie Chen and Vadivel Ganapathy. Performed the experiments: Zhiwei Chen, Xing Xia, Heyan Chen, Huirong Huang, Xingsi An and Sun Meng. Contributed new reagents or analytic tools: Yangzom D. Bhutia, Qing Yao, Kwonseop Kim and Hailin Zhang. Analyzed the data: Zhiwei Chen, Xing Xia and Heyan Chen.

Corresponding authors

Correspondence to Maoping Chu, Ruijie Chen or Longfa Kou.

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The animal studies were reviewed and approved by the Institutional Animal Care and Use Committee (approval number: wydw2019-0704).

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Chen, Z., Xia, X., Chen, H. et al. Carbidopa suppresses estrogen receptor-positive breast cancer via AhR-mediated proteasomal degradation of ERα. Invest New Drugs 40, 1216–1230 (2022). https://doi.org/10.1007/s10637-022-01289-5

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