The paradoxical functions of EGFR during breast cancer progression.
The paradoxical functions of EGFR during breast cancer progression.
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DOI：
10.1038/sigtrans.2016.42
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发表时间：
2017
影响因子：
39.3
通讯作者：
Wendt MK
中科院分区：
文献类型：
--
作者：
Ali R;Wendt MK
表皮生长因子受体(EGFR)是肿瘤进展过程中研究最深入的信号通路之一。因此，许多治疗药物被开发出来，包括小分子抑制剂和单抗，以针对这一关键的致癌驱动因素。其中几种EGFR抑制物(EGFRi)已经在转移性乳腺癌中进行了评估，因为原发肿瘤中高水平的EGFR表达与高度侵袭性的基底细胞样表型相关，并预测患者预后较差。令人惊讶的是，这些试验在改善患者预后方面一致失败。许多因素，例如缺乏适当的患者选择，可能是这些试验失败的原因之一。然而，最近的研究结果表明，在乳腺癌细胞的原发侵袭、扩散和最终转移过程中，EGFR信号发生了根本性的变化。在这里，我们回顾了针对EGFR的乳腺癌临床试验的结果，并探索了我们目前对原发性乳腺肿瘤中EGFR信号的理解，以及这些事件在转移环境中是如何改变的。总体而言，我们提出的假设是，原发肿瘤和转移性肿瘤之间EGFR信号的根本变化，即我们称之为“EGFR悖论”的过程，有助于临床观察到的对EGFRi的固有抵抗。此外，这一假设引入了利用EGFR激动剂作为治疗转移性乳腺癌的潜在治疗方法的可能性。
The epidermal growth factor receptor (EGFR) is one of the most well-studied signaling pathways in cancer progression. As a result, numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have been developed to target this critical oncogenic driver. Several of these EGFR inhibitors (EGFRi) have been evaluated in metastatic breast cancer, as high-level EGFR expression in primary tumors correlates with the highly aggressive basal-like phenotype and predicts for poor patient prognosis. Surprisingly, these trials have been unanimously unsuccessful at improving patient outcomes. Numerous factors, such as lack of proper patient selection may have contributed to the failure of these trials. However, recent findings suggest that there are fundamental changes in EGFR signaling that take place during primary tumor invasion, dissemination and ultimate metastasis of breast cancer cells. Herein, we review the outcomes of EGFR-targeted clinical trials in breast cancer and explore our current understanding of EGFR signaling within primary mammary tumors and how these events are altered in the metastatic setting. Overall, we put forth the hypothesis that fundamental changes in EGFR signaling between primary and metastatic tumors, a process we term the ‘EGFR paradox,’ contribute to the clinically observed inherent resistance to EGFRi. Furthermore, this hypothesis introduces the possibility of utilizing EGFR agonism as a potential therapeutic approach for the treatment of metastatic breast cancer.