Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.
Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.
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DOI：
10.1038/onc.2015.369
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发表时间：
2016-06-16
期刊：
影响因子：
8
通讯作者：
Ben-Jonathan N
中科院分区：
文献类型：
--
作者：
Borcherding DC;Tong W;Hugo ER;Barnard DF;Fox S;LaSance K;Shaughnessy E;Ben-Jonathan N
晚期乳腺癌患者通常对治疗没有反应，因此需要开发新的生物标志物和有效的治疗方法。多巴胺（DA）是一种与五种G蛋白偶联受体结合的儿茶酚胺。我们发现了DA 1型受体（D1 R）在乳腺癌中的表达，从而确定这些受体作为这种疾病的新的治疗靶点。751例原发性乳腺癌中有30%存在强至中度免疫反应性D1 R表达，并且与更大的肿瘤、更高的肿瘤分级、淋巴结转移和更短的患者生存期相关。DA和D1 R激动剂，通过cGMP/蛋白激酶G（PKG）途径的信号传导，抑制细胞活力，抑制侵袭，并诱导多种乳腺癌细胞系的凋亡。非诺多泮是一种外周D1 R激动剂，不穿透大脑，通过增加坏死和凋亡，在两种D1 R表达异种移植物的小鼠模型中显著抑制肿瘤生长。通过荧光成像检测小鼠中表达D1 R的原发肿瘤和转移瘤。总之，D1 R过表达与晚期乳腺癌和预后不良有关。D1 R/cGMP/PKG通路的激活在体外诱导细胞凋亡并在体内引起肿瘤缩小。FDA批准用于治疗肾性高血压的非诺多泮可以被重新用作D1 R表达肿瘤患者的新型治疗药物。
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 which binds to five G-protein-coupled receptors. We discovered expression of DA type-1 receptors (D1R) 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 which 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-approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors.
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