title: Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.
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.
authors.affiliation: Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Borcherding
authors.affiliation: Department of Pathology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Tong
authors.affiliation: Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Hugo
authors.affiliation: Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Barnard
authors.affiliation: Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Fox
authors.affiliation: Department of Radiology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: LaSance
authors.affiliation: Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: E
authors.initials: E
authors.lastname: Shaughnessy
authors.affiliation: Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ben-Jonathan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011954:Receptors, Dopamine / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine