Department of Gastrointestinal Surgery, Osaka University School of Medicine, Yamadaoka, Osaka, Japan.
Oncol Rep. 2010 Jan;23(1):35-43.
Whereas the Her2/neu/erbB2 receptor (Her2) could be a molecular target of the receptor-positive breast cancer, the therapeutic targets of Her2-negative cancer largely remain to be established. The expression of Her2 was evaluated in 48 primary breast cancer tumors by immunohistochemistry. The identified Notch pathway was studied in genotoxin-dependent suppression of breast cancer-initiating cell growth. Immunohistochemical assessment of Her2-negative tumors revealed significant association with overexpression of Notch1 and Notch3. Knockdown of Notch pathway resulted in sensitization of breast cancer cells to deionizing radiation, leading to cell death; the effect was more significant in stem marker CD44+ than in CD44- cells, and more profound in the Her2-negative than in positive cancer cells. The present study indicates that inhibition of Notch signaling could antagonize survival signal of Her2-negative breast cancer-initiating cells carrying genomic damage, and suggests that targeted suppression of the Notch pathway may give the rationale for sensitizing Her2-negative cancer-initiating cells to a therapeutic approach.
虽然 Her2/neu/erbB2 受体（Her2）可以作为受体阳性乳腺癌的分子靶点，但 Her2 阴性癌症的治疗靶点在很大程度上仍有待确定。通过免疫组织化学方法评估了 48 例原发性乳腺癌肿瘤中 Her2 的表达。在依赖遗传毒物抑制乳腺癌起始细胞生长的过程中，对 Notch 通路进行了研究。Her2 阴性肿瘤的免疫组织化学评估显示 Notch1 和 Notch3 的过表达有显著相关性。Notch 通路的敲低导致乳腺癌细胞对去离子辐射的敏感性增加，从而导致细胞死亡；在干细胞标志物 CD44+细胞中比 CD44-细胞中更显著，在 Her2 阴性肿瘤细胞中比阳性肿瘤细胞中更显著。本研究表明，抑制 Notch 信号通路可以拮抗携带基因组损伤的 Her2 阴性乳腺癌起始细胞的生存信号，并提示靶向抑制 Notch 通路可能为 Her2 阴性肿瘤起始细胞对治疗方法的敏感性提供依据。
