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Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer

Oncogene volume 35, pages 3103–3113 (2016)Cite this article

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Abstract

Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors.

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Acknowledgements

We dedicate this manuscript to Wilson Tong, M.D., whose untimely death was a major loss to all who knew him. We thank Dean Quaranta for technical assistance, and Drs Susan Waltz and Peter Stambrook for critical reviews of this manuscript. This investigation was funded by NIH grants CA096613 and ES020909, DOD grants AR110050 and BC122992, and pilot grants from Marlene Harris-Ride Cincinnati, and the University of Cincinnati Center for Clinical and Translational Science and Training (CCTST).

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Authors and Affiliations

  1. Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA

    D C Borcherding, E R Hugo, D F Barnard, S Fox & N Ben-Jonathan

  2. Department of Pathology, University of Cincinnati, Cincinnati, OH, USA

    W Tong

  3. Department of Radiology, University of Cincinnati, Cincinnati, OH, USA

    K LaSance

  4. Department of Surgery, University of Cincinnati, Cincinnati, OH, USA

    E Shaughnessy

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  1. D C Borcherding
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Correspondence to N Ben-Jonathan.

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Borcherding, D., Tong, W., Hugo, E. et al. Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer. Oncogene 35, 3103–3113 (2016). https://doi.org/10.1038/onc.2015.369

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