Notch pathway as candidate therapeutic target in Her2/Neu/ErbB2 receptor-negative breast tumors
Notch pathway as candidate therapeutic target in Her2/Neu/ErbB2 receptor-negative breast tumors
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DOI：
10.3892/or_00000603
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发表时间：
2010-01-01
期刊：
影响因子：
4.2
通讯作者：
Mori, Masaki
中科院分区：
文献类型：
--
作者：
Hirose, Hajime;Ishii, Hideshi;Mori, Masaki
虽然Her 2/neu/erbB 2受体（Her 2）可能是受体阳性乳腺癌的分子靶点，但Her 2阴性癌症的治疗靶点仍有待建立。应用免疫组化方法检测48例乳腺癌组织中Her 2的表达。研究了所鉴定的Notch途径在乳腺癌起始细胞生长的基因毒素依赖性抑制中的作用。Her 2阴性肿瘤的免疫组织化学评估显示Notch 1和Notch 3的过表达显著相关。Notch通路的敲除导致乳腺癌细胞对去电离辐射的敏感性，导致细胞死亡;干细胞标记物CD 44（+）细胞中的效应比CD 44（-）细胞中的效应更显著，Her 2阴性癌细胞中的效应比阳性癌细胞中的效应更显著。目前的研究表明，抑制Notch信号传导可以拮抗携带基因组损伤的Her 2阴性乳腺癌起始细胞的存活信号，并表明靶向抑制Notch通路可能为使Her 2阴性乳腺癌起始细胞对治疗方法敏感提供依据。
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.