Dopamine receptor Type 1 (D1R) in breast cancer: Expression, signaling, and therapeutic applications
Dopamine (DA) is a catecholamine which acts as a neurotransmitter in the brain and as a circulating hormone in the periphery. DA binds to five G-protein-coupled receptors, classified by their ability to increase cAMP (D1R and D2R) or decrease cAMP (D2R, D3R and D4R). We discovered D1R overexpression in breast cancer cell lines and tumors, thus identifying this receptor as a biomarker and a novel therapeutic target in breast cancer. Using tissue microarrays, D1R was overexpressed in 30% of 751 primary breast carcinomas, and was undetectable in normal breast tissue. D1R overexpression was associated with larger tumors, higher grades, node metastasis, and shorter patient survival. Unexpectedly, selective D1R agonists signal via the cGMP/protein kinase G (PKG) pathway. Activators of this pathway suppressed cell viability, inhibited cell invasion, increased chemosensitivity, and induced apoptosis in breast cancer cell lines. Fenoldopam, a peripheral D1R agonist which does not penetrate the brain, dramatically suppressed growth of D1R-expressing xenografts in two mouse models by increasing both apoptosis and necrosis. We also developed a fluorescent imaging method for D1R-expressing tumors and metastases in these mice. Ongoing studies are optimizing a positron emission tomography (PET) imaging for detecting D1Rexpressing tumors in patients.