Günthert Andreas R, Gründker Carsten, Olota Agnes, Läsche Julia, Eicke Nicola, Emons Günter
Department of Gynecology and Obstetrics, Georg-August-University, Robert-Koch-Street 40, D-37075 Göttingen, Germany.
Eur J Endocrinol. 2005 Oct;153(4):613-25. doi: 10.1530/eje.1.01996.
About 50-64% of human breast cancers express receptors for GnRH-I. Direct antiproliferative effects of analogs of GnRH-I on human breast cancer cell lines have been shown. They are at least in part mediated by antagonizing growth promoting effects of estradiol, epidermal growth factor (EGF) or insulin-like growth factor. Recently, expression of a putative receptor for GnRH-II in human tissues was demonstrated. Antiproliferative effects of GnRH-II in human endometrial and ovarian cancer cells were shown not to be mediated through the GnRH-I receptor. Now we demonstrate direct anti-proliferative effects of the GnRH-I analog Triptorelin and the GnRH-II analog [d-Lys(6)]GnRH-II in MCF-7 and T47D human breast cancer cells expressing GnRH-I receptors and putative GnRH-II receptors. Pretreatment with Triptorelin or [d-Lys(6)]GnRH-II blocked EGF-induced autophosphoryla-tion of EGF receptor and activation of mitogen-activated protein kinase (extracellular-signal-regulated kinase 1/2 (ERK1/2)) in these cells. In sublines of MCF-7 and T47D cells, which were developed to be resistant to 4OH-tamoxifen, HER-2/p185 was overexpressed. Pretreatment of these cell lines with Triptorelin or [d-Lys(6)]GnRH-II completely abolished resistance to 4OH-tamoxifen, assessed by 4OH-tamoxifen-induced apoptosis. Analogs of GnRH-I and GnRH-II counteract EGF-dependent signal transduction in human breast cancer cells with expression of receptors for GnRH-I and GnRH-II. Through this mechanism, they probably reverse acquired resistance to 4OH-tamoxifen mediated through overexpression or activation of receptors of the c-erbB family.
约50%-64%的人类乳腺癌表达促性腺激素释放激素I（GnRH-I）受体。已证实GnRH-I类似物对人乳腺癌细胞系具有直接的抗增殖作用。这些作用至少部分是通过拮抗雌二醇、表皮生长因子（EGF）或胰岛素样生长因子的促生长作用介导的。最近，已证实在人体组织中存在一种假定的促性腺激素释放激素II（GnRH-II）受体。已表明GnRH-II对人子宫内膜癌和卵巢癌细胞的抗增殖作用不是通过GnRH-I受体介导的。现在我们证明了GnRH-I类似物曲普瑞林和GnRH-II类似物[d-Lys(6)]GnRH-II对表达GnRH-I受体和假定的GnRH-II受体的MCF-7和T47D人乳腺癌细胞具有直接的抗增殖作用。用曲普瑞林或[d-Lys(6)]GnRH-II预处理可阻断这些细胞中EGF诱导的EGF受体自磷酸化以及丝裂原活化蛋白激酶（细胞外信号调节激酶1/2（ERK1/2））的激活。在对4-羟基他莫昔芬耐药的MCF-7和T47D细胞亚系中，HER-2/p185过表达。用曲普瑞林或[d-Lys(6)]GnRH-II预处理这些细胞系可完全消除对4-羟基他莫昔芬的耐药性，这是通过4-羟基他莫昔芬诱导的细胞凋亡来评估的。GnRH-I和GnRH-II类似物可抵消人乳腺癌细胞中依赖EGF的信号转导，这些细胞表达GnRH-I和GnRH-II受体。通过这种机制，它们可能逆转通过c-erbB家族受体的过表达或激活介导的对4-羟基他莫昔芬的获得性耐药。
