Membrane bound estrogen receptor GPR30 as therapeutic target for the triple-negative breast cancer (TNBC)

膜结合雌激素受体 GPR30 作为三阴性乳腺癌 (TNBC) 的治疗靶点

• 批准号: 218493294
• 负责人: Professor Dr. Carsten Gründker
• 金额: --
• 依托单位: Klinik für Geburtshilfe und Gynäkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/218493294?language=en
• 关键词: Membrane; bound; estrogen; receptor; GPR30

TNBCs lack estrogen receptor alpha (ERa), progesterone receptor (PR), and do not overexpress human epidermal growth factor receptor 2 (Her-2). They are neither susceptible to endocrine therapy nor to a therapy using anti-Her-2 antibody trastuzumab. Therefore, an efficient targeted therapy is warranted. TNBCs frequently express membrane bound estrogen receptor G-protein coupled receptor (GPR30). Apart from the classical genomic estrogen signaling via ERa, a non-genomic pathway via GPR30 exists. By transactivation of EGF receptor (EGF-R) GPR30 causes estrogen-induced activation of serum response element (SRE), whereby proliferation is finally promoted. Activation of growth hormone receptor (GH-R) induces expression of GPR30. We have examined two strategies, in order to use GPR30 as therapeutic target for treatment of TNBC. The 1st strategy was direct inhibition of GPR30, the 2nd strategy was inhibition of GPR30 expression using three different ways: 1.) Not only estrogens, but also anti-estrogens promote growth of TNBCs via GPR30. Estriol was proved as an efficient inhibitor of GPR30. GPR30 inhibition led to a clear reduction of stimulation of EGF-R signaling and thus proliferation. However, due to its low solubility Estriol is not applicable as a suitable inhibitor for clinical use. Better GPR30 antagonist should be developed. 2.) Inhibition of EGF-R tyrosine kinase by Gefitinib, activation of tyrosine phosphatase by GnRH analogs as well as inhibition of GH-R led to a clear reduction of GPR30 expression. Our results indicate that combination of inhibition of EGF-R and GH-R appears most promising. We would like to further investigate these strategies, to point out new ways for improvement of TNBC treatment. Moreover our results have to be examined in vivo, in order to prepare clinical studies.

TNBC缺乏雌激素受体α（ER α）、孕酮受体（PR），并且不过表达人表皮生长因子受体2（Her-2）。它们对内分泌治疗和使用抗Her-2抗体曲妥珠单抗的治疗均不敏感。因此，有效的靶向治疗是必要的。TNBC经常表达膜结合雌激素受体G蛋白偶联受体（GPR 30）。除了通过ER α的经典基因组雌激素信号传导外，还存在通过GPR 30的非基因组途径。通过EGF受体（EGF-R）的反式激活，GPR 30引起雌激素诱导的血清反应元件（SRE）的激活，从而最终促进增殖。生长激素受体（GH-R）的激活诱导GPR 30的表达。我们已经检查了两种策略，以使用GPR 30作为治疗TNBC的治疗靶标。第一种策略是直接抑制GPR 30，第二种策略是使用三种不同的方式抑制GPR 30表达：1.）不仅雌激素，而且抗雌激素通过GPR 30促进TNBC的生长。雌三醇被证明是GPR 30的有效抑制剂。GPR 30抑制导致EGF-R信号传导的刺激明显减少，从而导致增殖。然而，由于其低溶解度，雌三醇不适用于作为临床使用的合适抑制剂。因此，应开发更好的GPR 30拮抗剂。2.）的情况。Gefitinib对EGF-R酪氨酸激酶的抑制、GnRH类似物对酪氨酸磷酸酶的激活以及GH-R的抑制导致GPR 30表达明显降低。我们的研究结果表明，EGF-R和GH-R的联合抑制似乎最有希望。我们希望进一步研究这些策略，为改善TNBC治疗指出新的方法。此外，我们的结果必须在体内进行检查，以准备临床研究。