Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation.
Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation.
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DOI：
10.1158/0008-5472.can-13-1055
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发表时间：
2014-01-01
期刊：
影响因子：
11.2
通讯作者：
Diehn M
中科院分区：
文献类型：
--
作者：
Lee CY;Lin Y;Bratman SV;Feng W;Kuo AH;Scheeren FA;Engreitz JM;Varma S;West RB;Diehn M
目前，只有 HER2 阳性肿瘤患者才是 HER2 靶向治疗的候选者。然而，最近的临床观察表明，缺乏 HER2 扩增的 HER2 低乳腺癌患者的生存可能会受益于针对 HER2 的辅助治疗。在这项研究中，我们探索了一种可以获得这些好处的机制。在乳腺肿瘤起始细胞 (TIC) 中的 HER2/HER3 信号传导促进自我更新和存活的假设的推动下，我们获得了证据，表明 TIC 产生的神经调节蛋白 1 (NRG1) 可促进 HER2 低肿瘤（包括三阴性乳腺肿瘤）的增殖和自我更新。 EGFR、HER2 或两种受体的药物抑制可降低乳腺 TIC 的体外和体内存活和自我更新，并增加 TIC 对电离辐射的敏感性。通过组织微阵列分析，我们发现 NRG1 表达和相关的 HER2 激活发生在 HER2 低乳腺癌的子集中。我们的结果解释了为什么 HER2 抑制会阻止 HER2 低乳腺肿瘤的生长。此外，他们认为 EGFR 和 HER2 的双重抑制可能为这些肿瘤中的 TIC 提供一种有用的治疗策略。这项工作提出了在 HER2 低肿瘤患者中应用 HER2 靶向疗法的机制原理，表明了为什么这些疗法可以使比目前更多的乳腺癌患者受益。
Currently only patients with HER2-positive tumors are candidates for HER2-targeted therapies. However, recent clinical observations suggest that the survival of patients with HER2-low breast cancers, who lack HER2 amplification, may benefit from adjuvant therapy that targets HER2. In this study, we explored a mechanism through which these benefits may be obtained. Prompted by the hypothesis that HER2/HER3 signaling in breast tumor-initiating cells (TICs) promotes self-renewal and survival, we obtained evidence that neuregulin 1 (NRG1) produced by TICs promotes their proliferation and self-renewal in HER2-low tumors, including in triple-negative breast tumors. Pharmacologic inhibition of EGFR, HER2 or both receptors reduced breast TIC survival and self-renewal in vitro and in vivo and increased TIC sensitivity to ionizing radiation. Through a tissue microarray analysis, we found that NRG1 expression and associated HER2 activation occurred in a subset of HER2-low breast cancers. Our results offer an explanation for why HER2 inhibition blocks the growth of HER2-low breast tumors. Moreover, they argue that dual inhibition of EGFR and HER2 may offer a useful therapeutic strategy to target TICs in these tumors. In generating a mechanistic rationale to apply HER2 targeting therapies in patients with HER2-low tumors, this work shows why these therapies could benefit a considerably larger number of breast cancer patients than they currently reach.