Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 00215, USA.
Breast Cancer Res. 2011;13(6):R113. doi: 10.1186/bcr3055. Epub 2011 Nov 15.
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.
众所周知，烟草烟雾是导致肺癌、头颈部肿瘤的主要原因。最近，越来越多的证据表明，烟草烟雾暴露与乳腺癌风险增加有关。我们和其他研究小组已经表明，尼古丁作为一种非传统的致癌物质，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尚不清楚。在这里，我们研究了烟碱型乙酰胆碱受体（nAChR）的下游信号通路及其在乳腺癌促进中的作用。
我们使用人良性 MCF10A 和恶性 MDA-MB-231 乳腺细胞以及可能的下游激酶的特异性抑制剂，鉴定了尼古丁处理激活的 nAChR 效应器。我们进一步测试了这些效应通路对 E2F1 激活、细胞周期进程以及 Bcl-2 表达和长期细胞存活的调节作用。
在这项研究中，我们展示了一种新的信号机制，即尼古丁暴露通过激活Src 来敏化表皮生长因子受体（EGFR）介导的途径，促进乳腺癌细胞生长。在 nAChR 与尼古丁结合后，在 MCF10A 和 MDA-MB-231 乳腺癌细胞中均显示 EGFR 被激活并随后内化。随后，Src、Akt 和 ERK1/2 在尼古丁处理后不同时间点磷酸化。我们进一步证明，通过 Src，nAChR 与尼古丁的结合刺激了 EGFR/ERK1/2 通路，激活了 E2F1，并进一步促进了细胞进展。我们的数据还表明，Akt 直接位于 Src 的下游，负责增加 Bcl-2 的表达和长期细胞存活。
我们的研究揭示了一种潜在的调节网络的存在，该网络由尼古丁和 nAChR 的相互作用调控，整合了传统的促有丝分裂的 Src 和 EGFR 信号，用于乳腺癌的发生发展。
