Activation of the cGMP/protein kinase G system in breast cancer by the dopamine receptor-1

Despite recent advances in the detection and treatment of breast cancer, many shortcomings remain, providing incentives to search for new therapeutic targets. This review provides information on the expression and actions of dopamine receptor-1 (D1R) in breast cancer. D1R is overexpressed in a significant number of primary breast tumors, characterized by having an aggressive phenotype and predicting a shorter survival time for patients. Activation of D1R in breast cancer cells by selective agonists caused suppression of cell viability, stimulation of apoptosis, inhibition of cell invasion, and an increase in chemosensitivity. Instead of being linked to the cAMP/PKA system as expected, D1R in breast cancer is linked to the activation of the cGMP/protein kinase G (PKG) pathway. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed the growth of breast cancer xenografts in immune-deficient mice. A new imaging system for detecting D1R-expressing tumors and metastases was also developed. The review offers a novel concept that D1R can serve as a biomarker for prognosis in advanced breast cancer and its agonists can be used as effective and personalized therapeutics in a subpopulation of patients with D1R-expressing breast tumors. Several drugs, some of which are FDA-approved, that bypass the D1R and directly activate the cGMP/PKG apoptotic system, are also identified.