Santen Richard J, Song Robert X, Zhang Zhenguo, Yue Wei, Kumar Rakesh
Department of Medicine, University of Virginia Health Sciences System, Charlottesville, Virginia, USA.
Clin Cancer Res. 2004 Jan 1;10(1 Pt 2):337S-45S. doi: 10.1158/1078-0432.ccr-031207.
Clinical observations demonstrate that women with breast cancer often respond to subsequent endocrine manipulation after resistance to initial hormonal therapy develops. As a mechanistic explanation for these findings, we hypothesized that human breast tumors can adapt in response to the pressure exerted by endocrine therapy with development of hypersensitivity to estradiol. To understand the signaling pathways responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term deprivation of estradiol (LTED) causes adaptive hypersensitivity. Even though the estrogen receptor alpha (ERalpha) is markedly up-regulated in LTED cells, the enhanced responses to estradiol do not appear to involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found that ERalpha co-opts a classical growth factor pathway and induces rapid nongenomic effects that are enhanced in LTED cells. Estradiol binds to cell membrane-associated ERs, physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb2 and Sos, which result in the rapid activation of mitogen-activated protein kinase. These nongenomic effects of estradiol produced biological effects, as evidenced by Elk-1 activation and by morphological changes in cell membranes. The mechanistic pathways involved in adaptive hypersensitivity suggest that inhibitors of the mitogen-activated protein kinase and phosphatidylinositol-3-OH kinase pathways might prevent the development of adaptive hypersensitivity and allow more prolonged efficacy of endocrine therapies.
临床观察表明，乳腺癌女性患者在对初始激素治疗产生耐药性后，往往会对后续的内分泌治疗产生反应。作为对这些发现的机制性解释，我们假设人类乳腺肿瘤能够适应内分泌治疗所施加的压力，并对雌二醇产生超敏反应。为了了解其背后的信号通路，我们在一个模型系统中研究了雌激素对细胞增殖的刺激作用，并提供了体外和体内证据，证明长期剥夺雌二醇（LTED）会导致适应性超敏反应。尽管在LTED细胞中雌激素受体α（ERα）明显上调，但对雌二醇增强的反应似乎并不涉及作用于雌激素调节基因转录水平的机制。我们发现，ERα利用一条经典的生长因子途径，诱导快速的非基因组效应，这种效应在LTED细胞中增强。雌二醇与细胞膜相关的雌激素受体结合，与衔接蛋白Shc物理结合，并诱导其磷酸化。反过来，Shc与Grb2和Sos结合，导致丝裂原活化蛋白激酶的快速激活。雌二醇的这些非基因组效应产生了生物学效应，Elk-1激活和细胞膜形态变化证明了这一点。适应性超敏反应所涉及的机制途径表明，丝裂原活化蛋白激酶和磷脂酰肌醇-3-OH激酶途径的抑制剂可能会阻止适应性超敏反应的发生，并使内分泌治疗的疗效更持久。
