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

TNBCs缺乏雌激素受体α(ERA)、孕激素受体(PR)，不过度表达人表皮生长因子受体2(HER-2)。他们既不对内分泌治疗敏感，也不对使用抗HER-2抗体曲妥珠单抗治疗敏感。因此，有效的靶向治疗是必要的。TNBCs主要表达膜结合雌激素受体G蛋白偶联受体(GPR30)。除了经典的通过ERA的基因组雌激素信号外，还存在一条通过GPR30的非基因组途径。通过反式激活EGF受体(EGF-R)，GPR30引起雌激素诱导的血清反应元件(SRE)的激活，从而促进细胞增殖。生长激素受体(GH-R)的激活诱导GPR30的表达。为了将GPR30作为治疗TNBC的靶点，我们研究了两种策略。第一个策略是直接抑制GPR30，第二个策略是通过三种不同的方式抑制GPR30的表达：1)不仅雌激素，而且抗雌激素也通过GPR30促进TNBCs的生长。雌三醇被证明是GPR30的有效抑制剂。抑制GPR30可明显减少对EGF-R信号的刺激，从而抑制细胞增殖。然而，由于雌三醇的低溶解度，不适合作为一种适合临床使用的抑制剂。应开发更好的GPR30拮抗剂。2.)吉非替尼抑制EGF-R酪氨酸激酶，GnRH类似物激活酪氨酸磷酸酶，GH-R抑制GPR30的表达。我们的结果表明，联合抑制EGF-R和GH-R似乎是最有希望的。我们愿意进一步研究这些策略，为改善TNBC的治疗指出新的途径。此外，为了准备临床研究，我们的结果必须在体内进行检查。

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.