Sensitization of epithelial growth factor receptors by nicotine exposure to promote breast cancer cell growth.
Sensitization of epithelial growth factor receptors by nicotine exposure to promote breast cancer cell growth.
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DOI：
10.1186/bcr3055
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Chen CY
中科院分区：
文献类型：
--
作者：
Nishioka T;Kim HS;Luo LY;Huang Y;Guo J;Chen CY
众所周知，烟草烟雾是肺部、头部和颈部肿瘤的主要原因。最近，有证据表明，与烟草烟雾暴露有关的乳腺癌风险增加。我们和其他研究小组已经表明，尼古丁作为一种非传统致癌物质，有可能促进癌症的发生和发展。然而，烟雾影响乳房而不是肺部的潜在机制仍不清楚。在这里，我们研究可能的下游信号通路的烟碱乙酰胆碱受体（nAChR）及其在乳腺癌的促进作用。使用人类良性MCF 10A和恶性MDA-MB-231乳腺细胞和可能的下游激酶的特异性抑制剂，我们确定了尼古丁治疗激活的nAChR效应子。我们进一步测试了这些效应子通路对E2 F1激活、细胞周期进程以及Bcl-2表达和长期细胞存活的调节的影响。在这项研究中，我们证明了一种新的信号传导机制，尼古丁暴露激活Src敏感表皮生长因子受体（EGFR）介导的途径促进乳腺癌细胞的生长。nAChR与尼古丁连接后，EGFR被激活，然后在MCF 10A和MDA-MB-231乳腺癌细胞中内化。随后，Src、Akt和ERK 1/2在尼古丁处理后的不同时间点磷酸化。我们进一步证明，通过Src，尼古丁与nAChR的连接刺激了EGFR/ERK 1/2通路，从而激活E2 F1并进一步促进细胞进展。我们的数据还表明，Akt直接在Src下游发挥作用，并负责增加Bcl-2表达和长期细胞存活。我们的研究揭示了存在一个潜在的，由尼古丁和nAChR的相互作用，整合了传统的，促有丝分裂Src和EGFR信号乳腺癌的发展管理网络。
Tobacco smoke is known to be the main cause of lung, head and neck tumors. Recently, evidence for an increasing breast cancer risk associated with tobacco smoke exposure has been emerging. We and other groups have shown that nicotine, as a non-conventional carcinogen, has the potential to facilitate cancer genesis and progression. However, the underlying mechanisms by which the smoke affects the breast, rather than the lung, remain unclear. Here, we examine possible downstream signaling pathways of the nicotinic acetylcholine receptor (nAChR) and their role in breast cancer promotion. Using human benign MCF10A and malignant MDA-MB-231 breast cells and specific inhibitors of possible downstream kinases, we identified nAChR effectors that were activated by treatment with nicotine. We further tested the effects of these effector pathways on the regulation of E2F1 activation, cell cycle progression and on Bcl-2 expression and long-term cell survival. In this study, we demonstrated a novel signaling mechanism by which nicotine exposure activated Src to sensitize epidermal growth factor receptor (EGFR)-mediated pathways for breast cancer cell growth promotion. After the ligation of nAChR with nicotine, EGFR was shown to be activated and then internalized in both MCF10A and MDA-MB-231 breast cancer cells. Subsequently, Src, Akt and ERK1/2 were phosphorylated at different time points following nicotine treatment. We further demonstrated that through Src, the ligation of nicotine with nAChR stimulated the EGFR/ERK1/2 pathway for the activation of E2F1 and further cell progression. Our data also showed that Akt functioned directly downstream of Src and was responsible for the increase of Bcl-2 expression and long-term cell survival. Our study reveals the existence of a potential, regulatory network governed by the interaction of nicotine and nAChR that integrates the conventional, mitogenic Src and EGFR signals for breast cancer development.
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影响因子：
3.7
作者：
Real S;Meo-Evoli N;Espada L;Tauler A
通讯作者：
Tauler A
影响因子：
4
作者：
Nishioka, Takashi;Guo, Jinjin;Yamamoto, Daisuke;Chen, Lihua;Huppi, Petra;Chen, Chang Yan
通讯作者：
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影响因子：
15.9
作者：
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通讯作者：
Cooke, JP
影响因子：
6.4
作者：
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通讯作者：
Chellappan, Srikumar
影响因子：
4.8
作者：
Arredondo, Juan;Chernyavsky, Alexander I.;Grando, Sergei A.
通讯作者：
Grando, Sergei A.