Regulation of Breast Cancer Stem Cell Activity by Signaling through the Notch4 Receptor
Regulation of Breast Cancer Stem Cell Activity by Signaling through the Notch4 Receptor
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DOI：
10.1158/0008-5472.can-09-1681
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发表时间：
2010-01-15
期刊：
影响因子：
11.2
通讯作者：
Clarke, Robert B.
中科院分区：
文献类型：
--
作者：
Harrison, Hannah;Farnie, Gillian;Clarke, Robert B.
Notch受体信号通路不仅在正常乳腺发育中起重要作用，而且在乳腺癌的发生和发展中也起重要作用。我们评估了Notch受体在乳腺癌细胞系和9个原发性人类肿瘤样本中干细胞活性中的作用。通过选择抗失巢凋亡细胞或表达膜表型ESA（+）/CD 44（+）/CD 24（低）的细胞来富集干细胞。使用这些乳腺癌干细胞群体，我们比较了Notch受体的激活状态与腔分化细胞的状态，并评估了体外和体内途径抑制的后果。我们发现Notch 4信号活性在干细胞富集的细胞群中比分化细胞高8倍，而Notch 1信号活性在干细胞富集的细胞群中低4倍。Notch 1或Notch 4的药理学或遗传抑制降低了体外干细胞活性并减少了体内肿瘤形成，但Notch 4抑制产生了更强大的作用，观察到对肿瘤起始的完全抑制。我们的研究结果表明，Notch 4靶向治疗在抑制乳腺癌复发方面比Notch 1靶向治疗更有效，因为它是由乳腺癌干细胞启动的。Cancer Res; 70（2）; 709-18.（C）2010年AACR。
Notch receptor signaling pathways play an important role not only in normal breast development but also in breast cancer development and progression. We assessed the role of Notch receptors in stem cell activity in breast cancer cell lines and nine primary human tumor samples. Stem cells were enriched by selection of anoikis-resistant cells or cells expressing the membrane phenotype ESA(+)/CD44(+)/CD24(low). Using these breast cancer stem cell populations, we compared the activation status of Notch receptors with the status in luminally differentiated cells, and we evaluated the consequences of pathway inhibition in vitro and in vivo. We found that Notch4 signaling activity was 8-fold higher in stem cell-enriched cell populations compared with differentiated cells, whereas Notch1 signaling activity was 4-fold lower in the stem cell-enriched cell populations. Pharmacologic or genetic inhibition of Notch1 or Notch4 reduced stem cell activity in vitro and reduced tumor formation in vivo, but Notch4 inhibition produced a more robust effect with a complete inhibition of tumor initiation observed. Our findings suggest that Notch4-targeted therapies will be more effective than targeting Notch1 in suppressing breast cancer recurrence, as it is initiated by breast cancer stem cells. Cancer Res; 70(2); 709-18. (C)2010 AACR.