Department of Pathology, Loyola University Chicago, Maywood, IL 60153, USA.
Anticancer Res. 2010 Oct;30(10):3853-67.
Cancer stem cells (CSCs) are believed to be responsible for breast cancer formation and recurrence; therefore, therapeutic strategies targeting CSCs must be developed. One approach may be targeting signaling pathways, like Notch, that are involved in stem cell self-renewal and survival.
Breast cancer stem-like cells derived from cell lines and patient samples were examined for Notch expression and activation. The effect of Notch inhibition on sphere formation, proliferation, and colony formation was determined.
Breast cancer stem-like cells consistently expressed elevated Notch activation compared with bulk tumor cells. Blockade of Notch signaling using pharmacologic and genomic approaches prevented sphere formation, proliferation, and/or colony formation in soft agar. Interestingly, a gamma-secretase inhibitor, MRK003, induced apoptosis in these cells.
Our findings support a crucial role for Notch signaling in maintenance of breast cancer stem-like cells, and suggest Notch inhibition may have clinical benefits in targeting CSCs.
癌症干细胞（CSCs）被认为是导致乳腺癌形成和复发的罪魁祸首；因此，必须开发针对 CSCs 的治疗策略。一种方法可能是针对 Notch 等信号通路，这些通路参与干细胞自我更新和存活。
从细胞系和患者样本中鉴定出乳腺癌类干细胞，检测 Notch 的表达和激活情况。用 Notch 抑制物处理这些细胞，观察对球体形成、增殖和集落形成的影响。
乳腺癌类干细胞持续表达高水平的 Notch 激活，而 bulk tumor cells（肿瘤细胞团）则表达较低。用药物和基因方法阻断 Notch 信号通路，可阻止球体形成、增殖和/或软琼脂集落形成。有趣的是，一种γ-分泌酶抑制剂 MRK003 可诱导这些细胞凋亡。
我们的研究结果支持 Notch 信号在维持乳腺癌类干细胞中的关键作用，并表明 Notch 抑制可能在针对 CSCs 的治疗中有临床获益。
