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Oncogene. 2016 Jun 16;35(24):3103-13. doi: 10.1038/onc.2015.369. Epub 2015 Oct 19.

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

Author information

1
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
2
Department of Pathology, University of Cincinnati, Cincinnati, OH, USA.
3
Department of Radiology, University of Cincinnati, Cincinnati, OH, USA.
4
Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.

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.

PMID:
26477316
PMCID:
PMC5541367
DOI:
10.1038/onc.2015.369
[Indexed for MEDLINE]
Free PMC Article

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