Activation of mitogen-activated protein kinase in estrogen receptor α-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor α-negative human breast tumors
Activation of mitogen-activated protein kinase in estrogen receptor α-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor α-negative human breast tumors
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DOI：
10.1158/0008-5472.can-05-4363
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
El-Ashry, D
中科院分区：
文献类型：
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作者：
Creighton, CJ;Hilger, AM;El-Ashry, D
乳腺癌表现为雌激素受体α (ER α)阳性或阴性，ER α阳性的肿瘤对抗雌激素治疗有反应，预后较好。雌激素在ER α +乳腺癌细胞中调节的mRNA表达特征本身并不能解释ER α +和ER α -癌症之间观察到的巨大分子差异。在ER α -肿瘤中，观察到表皮生长因子受体（EGFR）或c-erbB-2的过度表达，导致生长因子信号传导增加，因此与ER α -阳性乳腺癌相比，丝裂原活化蛋白（MAP）激酶（MAPK）显着过度活化。在内质网α +/孕酮受体阳性、雌激素依赖的MCF-7乳腺癌细胞中，我们稳定地过表达EGFR或组成性活性erbB-2、Raf或MAP/细胞外信号调节激酶激酶，导致细胞系表现出MAPK的过度激活、不依赖雌激素的生长和内质网α表达的可逆下调。通过全球mRNA分析，我们发现在每个MAPK+细胞系中，大约有400个基因的“MAPK特征”持续上调或下调。在几个独立的人类乳腺肿瘤数据集中，体外MAPK标记能够准确区分ER+和ER-肿瘤。此外，我们的体外mRNA谱数据揭示了erbB-2或EGFR激活特有的mBNA特征。的一个子集。发现乳腺肿瘤特征与erbb -2特异性或egfr特异性特征具有广泛的相似性。我们的研究结果证实，MAPK激活的增加导致ER α表达的丧失，并表明MAPK的过度激活在乳腺癌中ER α -表型的产生中起作用。这些MAPK+细胞系是研究内质网α -表型背后潜在机制的绝佳模型。
Breast cancer presents as either estrogen receptor alpha (ER alpha) positive or negative, with ER alpha+ tumors responding to antiestrogen therapy and having a better prognosis. By themselves, mRNA expression signatures of estrogen regulation in ER alpha+ breast cancer cells do not account for the vast molecular differences observed between ER alpha+ and ER alpha- cancers. In ER alpha- tumors, overexpression of epidermal growth factor receptor (EGFR) or c-erbB-2, leading to increased growth factor signaling,, is observed such that mitogen-activated protein (MAP) kinase (MAPK) is significantly hyperactivated compared with ER alpha+ breast cancer. In ER alpha+/progesterone receptor-positive, estrogen-dependent MCF-7 breast cancer cells, we stably overexpressed EGFR or constitutively active erbB-2, Raf, or MAP/extracellular signal-regulated kinase kinase, resulting in cell lines exhibiting hyperactivation of MAPK, estrogen-independent growth, and the reversible down-regulation of ER alpha expression. By global mRNA profiling, we found a "MAPK signature" of similar to 400 genes consistently up-regulated or down-regulated in each of the MAPK+ cell lines. In several independent profile data sets of human breast tumors, the in. vitro MAPK signature was able to accurately distinguish ER+ from ER- tumors. In addition, our in vitro mRNA profile data revealed distinct mBNA signatures specific to either erbB-2 or EGFR activation. A subset. of breast tumor profiles was found to share extensive similarities with either the erbB-2-specific or the EGFR-specific signatures. Our results confirm that, increased MAPK activation causes loss of ER alpha expression and suggest that hyperactivation of MAPK plays a role in the generation of the ER alpha- phenotype in breast cancer. These MAPK+ cell lines are excellent models for investigating the underlying mechanisms behind the ER alpha- phenotype.