Aurora A Kinase Regulates Mammary Epithelial Cell Fate by Determining Mitotic Spindle Orientation in a Notch-Dependent Manner

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. [Display omitted] •Aurora A kinase regulates mitotic spindle orientation in the mammary epithelium•Orientation perpendicular to the basement membrane is dependent on Notch activity•Blocking Aurora A-TPX2 interaction or Notch activity promotes parallel orientation•Parallel orientation promotes the basal, and perpendicular the luminal, cell lineages The mechanisms of cell lineage determination in the mammary gland remain a subject of intense debate. In this study, Smalley and colleagues show that the mitotic kinase Aurora A regulates the orientation of cell division in the growing tips of the mammary epithelial ducts to send cells into different epithelial lineages. Remarkably, Notch signaling was required for promotion of the luminal lineage, whereas blocking of Notch promoted the basal lineage. These findings place Aurora A and Notch upstream of the regulation of the mitotic spindle.