Division of Breast Cancer Research, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Cell Rep. 2013 Jul 11;4(1):110-23. doi: 10.1016/j.celrep.2013.05.044. Epub 2013 Jun 27.
Cell fate determination in the progeny of mammary epithelial stem/progenitor cells remains poorly understood. Here, we have examined the role of the mitotic kinase Aurora A (AURKA) in regulating the balance between basal and luminal mammary lineages. We find that AURKA is highly expressed in basal stem cells and, to a lesser extent, in luminal progenitors. Wild-type AURKA expression promoted luminal cell fate, but expression of an S155R mutant reduced proliferation, promoted basal fate, and inhibited serial transplantation. The mechanism involved regulation of mitotic spindle orientation by AURKA and the positioning of daughter cells after division. Remarkably, this was NOTCH dependent, as NOTCH inhibitor blocked the effect of wild-type AURKA expression on spindle orientation and instead mimicked the effect of the S155R mutant. These findings directly link AURKA, NOTCH signaling, and mitotic spindle orientation and suggest a mechanism for regulating the balance between luminal and basal lineages in the mammary gland.
乳腺上皮干细胞/祖细胞后代的细胞命运决定仍知之甚少。在这里，我们研究了有丝分裂激酶 Aurora A（AURKA）在调节基底和腔上皮乳腺谱系之间平衡中的作用。我们发现 AURKA 在基底干细胞中高度表达，在腔祖细胞中表达较少。野生型 AURKA 表达促进了腔细胞命运，但 S155R 突变体的表达减少了增殖，促进了基底命运，并抑制了连续移植。该机制涉及 AURKA 调节有丝分裂纺锤体取向以及分裂后子细胞的定位。值得注意的是，这是 NOTCH 依赖性的，因为 NOTCH 抑制剂阻断了野生型 AURKA 表达对纺锤体取向的影响，反而模拟了 S155R 突变体的作用。这些发现直接将 AURKA、NOTCH 信号和有丝分裂纺锤体取向联系起来，并为调节乳腺中腔和基底谱系之间的平衡提供了一种机制。
