Aurora kinase A enables collective invasion by endowing a leader cell phenotype and stabilizing EPLIN-mediated cohesion with follower cells

Breast cancer is one of the most commonly diagnosed cancers and one of the leading causes of cancer-related mortality worldwide. Despite advances in treatment, the 5-year survival of patients with metastatic breast cancer can be as low as 9%. Collective migration describes cells migrating as a group rather than as individuals and is the predominant mode of migration by cancer cells. In the cells leading a migrating cluster of cells, termed leader cells, Aurora kinase A (AURKA) has been found to be highly expressed, and its expression is elevated in multiple cancers, including breast cancer. Although it is known that AURKA may play a role in collective migration and some functions have been elucidated, its specific functions in the leader cell to drive collective migration and metastasis are not fully understood. I investigated the roles of AURKA in collective migration and metastasis in MCF10A cells, a breast epithelial cell line isolated from human fibrocystic breast tissue. In vivo studies in chick embryos demonstrated that the expression of GFP-AURKA in MCF10A cells endowed an ability to metastasize. Analysis of the migration of MCF10A cells expressing GFP-AURKA revealed the establishment of leader cells and increased collective migration. Consistent with this observation, the addition of an AURKA inhibitor, MLN8237, significantly decreased collective migration and led to an increase in cell scattering. Immunofluorescence and live-cell imaging analysis suggested that AURKA may regulate the stability of E-cadherin and adherens junctions by interacting with the epithelial protein lost in neoplasm (EPLIN), an actin-binding protein that plays a role in cell motility and stabilizes cell-cell contacts. These findings highlight the importance of AURKA in driving collective migration and metastasis, and support the development of therapies to target AURKA activity to prevent and treat metastatic breast cancer.