The Nek2 Mitotic Kinase Drives Centrosome Amplification, Mitotic Dysfunction, And Invasion In Mammary Epithelial And Breast Cancer Cells

Despite findings reported by The Cancer Genome Atlas (TCGA) that the most common human tumors have undergone at least one genomic doubling, the roles of polyploidy and chromosome instability (CIN) in cancer are poorly understood. Defective mitosis, and centrosome amplification (CA) are major sources of CIN, which generally associates with poor prognosis of patients. Prevalence of CA and CIN in hormone receptor negative (ER-PR-Her2- or ER-PR-Her2+) breast cancer patients, who have the poorest outcomes among all intrinsic subtypes, suggest that CA and CIN play major roles in the disease. CA in breast cancers correlates with poor survival, metastasis and high tumor grade, suggesting roles in tumor progression. Our laboratory, using an inducible K-RasG12D transgenic mouse that directed its expression to mammary epithelial cells, demonstrated CA appeared in precancerous mammary epithelial lesions, suggesting a role in tumor initiation. Despite these observations, the role of CA as cancer driver or promoter has not been tested experimentally. To understand that role, drivers of CA in cancer must be identified, and our laboratory showed that dysregulated E2F1, E2F2 and E2F3a, and their mitotic targets, including Nek2, TTK, and SgoI sustain CA and CIN in mammary epithelial and breast cancer cells. In fact, orthotopic models of breast cancer demonstrated that silencing of E2F3 leads to slow tumor growth that correlates with reduced mitosis, CA and Nek2 levels. We find that overexpression of the E2F target Nek2 in non-transformed mammary epithelial cells results in large acinar structures, CA, CIN, and changes in relevant EMT markers that include vimentin. Our findings indicate that deregulated E2F pathway contribute to mammary tumorigenesis in part by deregulating kinases that control mitosis, including Nek2, and in turn these affect mitotic progression, CIN, EMT and invasion. Thus, centrosome/kinases downstream of the E2F pathway may represent future targets for intervention in highly-malignant HR- breast cancers. Citation Format: Yainyrette Rivera-Rivera, Mihaela Marina, Miyoung Lee, Harold I. Saavedra. The Nek2 mitotic kinase drives centrosome amplification, mitotic dysfunction, and invasion in mammary epithelial and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3461. doi:10.1158/1538-7445.AM2017-3461