Wang Zhaoyi, Zhang Xintian, Shen Peng, Loggie Brian W, Chang Yunchao, Deuel Thomas F
Cancer Center, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9063-8. doi: 10.1073/pnas.0603339103. Epub 2006 Jun 5.
The status of the 66-kDa human estrogen receptor-alpha (hER-alpha66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human breast cancer. Recently, we cloned the cDNA of an alternatively spliced variant of hER-alpha66, termed hER-alpha36; the predicted protein lacks both transcriptional activation domains of hER-alpha66 but retains its DNA-binding domain, partial dimerization, and ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-alpha36 functions very differently from hER-alpha66 in response to estrogen signaling. We now demonstrate that hER-alpha36 inhibits the estrogen-dependent and estrogen-independent transactivation activities of hER-alpha66 and hER-beta. We further demonstrate that hER-alpha36 is predominantly associated with the plasma membrane where it transduces both estrogen- and antiestrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-alpha36 is a predominantly membrane-based, unique alternatively spliced variant of hER-alpha66 that acts as a dominant-negative effector of both estrogen-dependent and estrogen-independent transactivation functions signaled through hER-alpha66 and ER-beta; it also transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase mitogenic signaling pathway. The estrogen and antiestrogen signaling pathways mediated by hER-alpha36 provide an alternative explanation for why some human breast cancers are resistant to and others are worsened by antiestrogen therapy; the data suggest that hER-alpha36 also may be an important marker to direct therapy in human breast cancers, and perhaps hER-alpha36 also may transduce estrogen-dependent signaling in other estrogen target tissues.
66 kDa人雌激素受体α（hER-α66）的状态是评估人类乳腺癌预后和设计治疗策略的关键决定因素。最近，我们克隆了hER-α66的一种选择性剪接变体的cDNA，称为hER-α36；预测的蛋白质缺乏hER-α66的两个转录激活结构域，但保留了其DNA结合结构域、部分二聚化结构域和配体结合结构域以及位于N端附近的三个潜在肉豆蔻酰化位点。因此，这些发现预测hER-α36在雌激素信号传导反应中的功能与hER-α66非常不同。我们现在证明hER-α36抑制hER-α66和hER-β的雌激素依赖性和雌激素非依赖性反式激活活性。我们进一步证明hER-α36主要与质膜相关，在质膜上它转导雌激素和抗雌激素依赖性的丝裂原活化蛋白激酶/细胞外信号调节激酶信号通路的激活并刺激细胞生长。我们得出结论，hER-α36是hER-α66的一种主要基于膜的独特选择性剪接变体，它作为通过hER-α66和ER-β发出信号的雌激素依赖性和雌激素非依赖性反式激活功能的显性负效应物；它还转导膜起始的雌激素依赖性丝裂原活化蛋白激酶/细胞外信号调节激酶有丝分裂信号通路的激活。由hER-α36介导的雌激素和抗雌激素信号通路为为什么一些人类乳腺癌对抗雌激素治疗耐药而另一些则因抗雌激素治疗而恶化提供了另一种解释；数据表明hER-α36也可能是指导人类乳腺癌治疗的重要标志物，也许hER-α36也可能在其他雌激素靶组织中转导雌激素依赖性信号传导。
