Generic placeholder image

Current Drug Discovery Technologies


ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

The Expression of Dopamine Receptors Gene and their Potential Role in Targeting Breast Cancer Cells with Selective Agonist and Antagonist Drugs. Could it be the Novel Insight to Therapy?

Author(s): Hossein Bakhtou, Asiie Olfatbakhsh, Abdolkhaegh Deezagi and Ghasem Ahangari*

Volume 16 , Issue 2 , 2019

Page: [184 - 197] Pages: 14

DOI: 10.2174/1570163815666180130101421

Price: $65


Background: Breast cancer is one of the common causes of mortality for women in Iran and other parts of the world. The substantial increasing rate of breast cancer in both developed and developing countries warns the scientists to provide more preventive steps and therapeutic measures. This study is conducted to investigate the impact of neurotransmitters (e.g., Dopamine) through their receptors and the importance of cancers via damaging immune system. It also evaluates dopamine receptors gene expression in the women with breast cancer at stages II or III and dopamine receptor D2 (DRD2) related agonist and antagonist drug effects on human breast cancer cells, including MCF-7 and SKBR-3.

Methods: The patients were categorized into two groups: 30 native patients who were diagnosed with breast cancer at stages II and III, with the mean age of 44.6 years and they were reported to have the experience of a chronic stress or unpleasant life event. The second group included 30 individuals with the mean age of 39 years as the control group. In order to determine the RNA concentration in all samples, the RNA samples were extracted and cDNA was synthesized. The MCF-7 cells and SKBR-3 cells were treated with dopamine receptors agonists and antagonists. The MTT test was conducted to identify oxidative and reductive enzymes and to specify appropriate dosage at four concentrations of dopamine and Cabergoline on MCF-7 and SKBR-3 cells. Immunofluorescence staining was done by the use of a mixed dye containing acridine orange and ethidiume bromide on account of differentiating between apoptotic and necrotic cells. Flow cytometry assay was an applied method to differentiate necrotic from apoptotic cells.

Results: Sixty seven and thirty three percent of the patients were related to stages II and III, respectively. About sixty three percent of the patients expressed ER, while fifty seven percent expressed PR. Thirty seven percent of the patients were identified as HER-2 positive. All types of D2-receptors were expressed in PBMC of patients with breast cancer and healthy individuals. The expression of the whole dopamine receptor subtypes (DRD2-DRD4) was carried out on MCF-7 cell line. The results of RT-PCR confirmed the expression of DRD2 on SKBR-3 cells, whereas the other types of D2- receptors did not have an expression. The remarkable differences in gene expression rates between patients and healthy individuals were revealed in the result of the Real-time PCR analysis. The over expression in DRD2 and DRD4 genes of PBMCs was observed in the patients with breast cancer at stages II and III. The great amount of apoptosis and necrosis occurred after the treatment of MCF-7 cells by Cabergoline from 25 to 100 µmolL-1 concentrations.

Conclusion: This study revealed the features of dopamine receptors associated with apoptosis induction in breast cancer cells. Moreover, the use of D2-agonist based on dopamine receptors expression in various breast tumoral cells could be promising as a new insight of complementary therapy in breast cancer.

Keywords: Agonist, antagonist, apoptosis, breast cancer, cabergoline, dopamine receptors.

Graphical Abstract
DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, racial disparity in mortality by state. CA Cancer J Clin 2017; 67: 439-48.
Anothaisintawee T, Wiratkapun C, Lerdsitthichai P, et al. Risk factors of breast cancer: A systematic review and meta-analysis. Asia Pac J Public Health 2013; 25(5): 368-87.
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve—an integrative interface between two supersystems: The brain and the immune system. Pharmacol Rev 2002; 52: 595-638.
Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA 2007; 298: 1685-7.
Barik J, Marti F, Morel C, et al. Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons. Science 2013; 339: 332-5.
Yuan A, Wang S, Li Z, Huang C. Psychological aspect of cancer from stressor to cancer progression. Exp Ther Med 2010; 11: 13-8.
Vallone D, Picetti R, Borrelli E. Structure and function of dopamine receptors. Neurosci Biobehav Rev 2000; 241: 125-32.
Mancino M, Ametller E, Gascón P, Almendro V. The neuronal influence on tumor progression. Biochim Biophys Acta 2011; 1816: 105-18.
Beaulieu J-M, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011; 63: 182-217.
Jafari M, Ahangari G, Saberi M, et al. Distorted expression of dopamine receptor genes in systemic lupus erythematosus. Immunobiology 2013; 218: 979-83.
Matthew T, Charlene S, Albert B. The effects of dopamine receptor 2 on breast cancer tumor initiating cells. [abstract]. Proceedings of the 107th Annual Meeting of the American Association for CancerResearch; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016; 76(14 Suppl): Abstract nr 3316.
Gholipour N, Ohradanova-Repic A, Ahangari G. A novel report of MiR‐4301 induces cell apoptosis by negatively regulating DRD2 expression in human breast cancer cells. J Cell Biochem 2018; 119(8): 6408-17.
Shaikhpoor MAGSM. Significant changes in D2-like dopamine gene receptors expression associated with Non- small -cell lung cancer: could it be of potential use in the design of future therapeutic strategies? Curr Cancer Ther Rev 2012; 8: 304-10.
Basu B, Sarkar C, Chakroborty D, et al. D1 and D2 dopamine receptor-mediated inhibition of activated normal T cell proliferation is lost in jurkat T leukemic cells. J Biol Chem 2010; 285: 27026-32.
Pornour M, Ahangari G, Hejazi S, Ahmadkhaniha H, Akbari M. Dopamine receptor gene (DRD1-DRD5) expression changes as stress factors associated with breast cancer. Asian Pac J Cancer Prev: APJCP 2014; 15: 10339.
Bhatia M, Sachlos E, Risueno RM. Treatment of cancer with dopamine receptor antagonists. EP2680853A1 2014.
Pijl H, Ohashi S, Matsuda M. A novel approach to the treatment of type 2 diabetes. Diabetes Care 2000; 23: 1154-61.
Kline CLB, Ralff MD, Lulla AR, et al. Role of Dopamine receptors in the anticancer activity of ONC201. Neoplasia 2018; 20(1): 80-91.
Li J, Yao QY, Xue JS, et al. Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer. Acta Pharmacol Sin 2017; 38: 1282-96.
Sarkar C, Chakroborty D, Chowdhury UR, Dasgupta PS, Basu S. Dopamine increases the efficacy of anticancer drugs in breast and colon cancer preclinical models. Clin Cancer Res 2008; 14: 2502-10.
Minami K, Liu S, Liu Y, et al. Inhibitory effects of dopamine receptor D1 agonist on mammary tumor and bone metastasis. Sci Rep 2017; 7: 45686.
Ghasem A, Majid P, Hossein B, et al. Significant association between Catechol Amine O-Methyl Transferase (COMT) gene expression changes and breast cancer pathogenesis. J Carcinog Mutagen 2015; 6: 2.
Hoeppner LH, Wang Y, Sharma A, et al. Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells. Mol Oncol 2015; 9: 270-81.
Basu S, Nagy JA, Pal S, et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med 2001; 7: 569-74.
De Leeuw Van Weenen JPE, Maechler P, et al. The dopamine receptor D2 agonist Bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the α2-adrenergic receptors in beta cells. Biochem Pharmacol 2010; 79: 1827-36.
Rai S, Tanaka H, Suzuki M, et al. Chlorpromazine, an inhibitor of intracellular trafficking of FLT3-ITD and KIT D816V, shows prominent anti-leukemic activities against AML cells and AML stem cells in vitro and in vivo. Blood 2014; 124: 269.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy