Breast Biology Group, School of Cancer, Enabling Sciences and Technology, Paterson Institute for Cancer Research, University of Manchester, Manchester Academic Health Sciences Centre, The Christie NHS Foundation Trust; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom.
Cancer Res. 2010 Jan 15;70(2):709-18. doi: 10.1158/0008-5472.CAN-09-1681. Epub 2010 Jan 12.
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.
Notch 受体信号通路不仅在正常乳腺发育中起着重要作用，而且在乳腺癌的发生和发展中也起着重要作用。我们评估了 Notch 受体在乳腺癌细胞系和九个人类原发性肿瘤样本中的干细胞活性中的作用。通过选择抗 anoikis 的细胞或表达膜表型 ESA(+) / CD44(+) / CD24(low)的细胞来富集干细胞。利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细胞分化状态，并评估了体外和体内途径抑制的后果。我们发现，与分化细胞相比，富含干细胞的细胞群体中 Notch4 信号活性高 8 倍，而 Notch1 信号活性在富含干细胞的细胞群体中低 4 倍。Notch1 或 Notch4 的药物或遗传抑制在体外降低了干细胞活性，并减少了体内肿瘤形成，但 Notch4 抑制产生了更显著的效果，观察到完全抑制肿瘤起始。我们的研究结果表明，与靶向 Notch1 相比，针对 Notch4 的治疗方法将更有效地抑制乳腺癌复发，因为它是由乳腺癌干细胞引发的。
