University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
Cancer Res. 2013 Jun 15;73(12):3489-93. doi: 10.1158/0008-5472.CAN-13-0260. Epub 2013 Jun 5.
The development of HER2 targeting agents has dramatically altered the natural history of HER2-positive breast cancer and is often cited as a prime example of the effectiveness of molecularly targeted therapy. Emerging data suggest that the remarkable clinical efficacy of these agents may be related to their ability to target the breast cancer stem cell (CSC) population. A new study suggests that the regulation of BCSCs by HER2 may extend to breast cancers that do not display HER2 gene amplification. In these tumors, HER2 is selectively expressed in the CSC population, and this expression is regulated by the tumor microenvironment. In mouse models, trastuzumab blocked growth of these HER2-negative tumors when administered in the adjuvant setting but had no effect on established tumors. These studies provide a potential biologic explanation for retrospective analysis of clinical trials, which surprisingly suggest that the clinical benefits of adjuvant trastuzumab may extend to women currently classified as HER2-negative. In addition to having significant implications for breast cancer therapy, these studies suggest the need to reevaluate the role of HER2 in regulating CSCs in other tumor types. Furthermore, these studies suggest that effective adjuvant therapies may need to target the CSC population.
曲妥珠单抗等 HER2 靶向药物的发展显著改变了 HER2 阳性乳腺癌的自然病程，常被作为分子靶向治疗有效性的典范。新出现的数据提示，这些药物的显著临床疗效可能与其靶向乳腺癌干细胞（CSC）群体的能力相关。一项新研究提示，HER2 对 CSCs 的调节可能延伸至不显示 HER2 基因扩增的乳腺癌。在这些肿瘤中，HER2 在 CSC 群体中选择性表达，这种表达受肿瘤微环境调控。在小鼠模型中，曲妥珠单抗在辅助治疗环境下应用时可阻断这些 HER2 阴性肿瘤的生长，但对已建立的肿瘤无影响。这些研究为临床试验的回顾性分析提供了一个潜在的生物学解释，令人惊讶的是，这些分析提示辅助曲妥珠单抗的临床获益可能延伸至目前被归类为 HER2 阴性的女性。这些研究除了对乳腺癌治疗具有重要意义外，还提示需要重新评估 HER2 在调节其他肿瘤类型 CSCs 中的作用。此外，这些研究提示有效的辅助治疗可能需要靶向 CSC 群体。
