%0 Journal Article %A Chu, Tony L.H. %A Connell, Marisa %A Zhou, Lixin %A He, Zhengcheng %A Won, Jennifer %A Chen, Helen %A Rahavi, Seyed M.R. %A Mohan, Pooja %A Nemirovsky, Oksana %A Fotovati, Abbas %A Pujana, Miguel Angel %A Reid, Gregor S.D. %A Nielsen, Torsten O. %A Pante, Nelly %A Maxwell, Christopher A. %T Cell Cycle–Dependent Tumor Engraftment and Migration Are Enabled by Aurora-A %D 2018 %R 10.1158/1541-7786.MCR-17-0417 %J Molecular Cancer Research %P 16-31 %V 16 %N 1 %X Cell-cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell-cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multiparameter imaging of wound closure assays was used to track cell-cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell-cycle indicator. Cell migration occurred with an elevated velocity and directionality during the S–G2-phase of the cell cycle, and cells in this phase possess front-polarized centrosomes with augmented microtubule nucleation capacity. Inhibition of Aurora kinase-A (AURKA/Aurora-A) dampens these phenotypes without altering cell-cycle progression. During G2-phase, the level of phosphorylated Aurora-A at centrosomes is reduced in hyaluronan-mediated motility receptor (HMMR)-silenced cells as is the nuclear transport of TPX2, an Aurora-A–activating protein. TPX2 nuclear transport depends upon HMMR-T703, which releases TPX2 from a complex with importin-α (KPNA2) at the nuclear envelope. Finally, the abundance of phosphorylated HMMR-T703, a substrate for Aurora-A, predicts breast cancer–specific survival and relapse-free survival in patients with estrogen receptor (ER)–negative (n = 941), triple-negative (TNBC) phenotype (n = 538), or basal-like subtype (n = 293) breast cancers, but not in those patients with ER-positive breast cancer (n = 2,218). Together, these data demonstrate an Aurora-A/TPX2/HMMR molecular axis that intersects cell-cycle progression and cell migration.Implications: Tumor cell engraftment, migration, and cell-cycle progression share common regulation of the microtubule cytoskeleton through the Aurora-A/TPX2/HMMR axis, which has the potential to influence the survival of patients with ER-negative breast tumors. Mol Cancer Res; 16(1); 16–31. ©2017 AACR. %U https://mcr.aacrjournals.org/content/molcanres/16/1/16.full.pdf