RT Journal Article SR Electronic T1 Cell Cycle–Dependent Tumor Engraftment and Migration Are Enabled by Aurora-A JF Molecular Cancer Research JO Mol Cancer Res FD American Association for Cancer Research SP 16 OP 31 DO 10.1158/1541-7786.MCR-17-0417 VO 16 IS 1 A1 Chu, Tony L.H. A1 Connell, Marisa A1 Zhou, Lixin A1 He, Zhengcheng A1 Won, Jennifer A1 Chen, Helen A1 Rahavi, Seyed M.R. A1 Mohan, Pooja A1 Nemirovsky, Oksana A1 Fotovati, Abbas A1 Pujana, Miguel Angel A1 Reid, Gregor S.D. A1 Nielsen, Torsten O. A1 Pante, Nelly A1 Maxwell, Christopher A. YR 2018 UL http://mcr.aacrjournals.org/content/16/1/16.abstract AB 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.