E2F Activators Signal and Maintain Centrosome Amplification in Breast Cancer Cells

• Type of Material: Article
• Authors: Mi-Young Lee, Emory University; Carlos S Moreno, Emory University; Harold Saavedra, Emory University
• Language: English
• Date: 2014-07-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2014, American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/MCB.01688-13
• Title of Journal or Parent Work: Molecular and Cellular Biology
• ISSN: 0270-7306
• Volume: 34
• Issue: 14
• Start Page: 2581
• End Page: 2599
• Grant/Funding Information: This research project was supported by R01 CA151521 from the National Institutes of Health.
• Keywords: Life Sciences & Biomedicine; CHROMOSOMAL INSTABILITY; Science & Technology; FAMILY-MEMBERS; CELLULAR PROLIFERATION; BIOCHEMISTRY & MOLECULAR BIOLOGY; CYCLIN D1; COLON-CANCER; LUNG-CARCINOMA; TRANSCRIPTION FACTOR; OVARIAN-CANCER; CELL BIOLOGY; S-PHASE; COMPARATIVE GENOMIC HYBRIDIZATION; Biochemistry & Molecular Biology; Cell Biology
• Research Categories: Health Sciences, Radiology; Health Sciences, Oncology; Health Sciences, Pathology

Abstract

Centrosomes ensure accurate chromosome segregation by directing spindle bipolarity. Loss of centrosome regulation results in centrosome amplification, multipolar mitosis and aneuploidy. Since centrosome amplification is common in premalignant lesions and breast tumors, it is proposed to play a central role in breast tumorigenesis, a hypothesis that remains to be tested. The coordination between the cell and centrosome cycles is of paramount importance to maintain normal centrosome numbers, and the E2Fs may be responsible for regulating these cycles. However, the role of E2F activators in centrosome amplification is unclear. Because E2Fs are deregulated in Her2+ cells displaying centrosome amplification, we addressed whether they signal this abnormal process. Knockdown of E2F1 or E2F3 in Her2+ cells decreased centrosome amplification without significantly affecting cell cycle progression, whereas the overexpression of E2F1, E2F2, or E2F3 increased centrosome amplification in MCF10A mammary epithelial cells. Our results revealed that E2Fs affect the expression of proteins, including Nek2 and Plk4, known to influence the cell/centrosome cycles and mitosis. Downregulation of E2F3 resulted in cell death and delays/blocks in cytokinesis, which was reversed by Nek2 overexpression. Nek2 overexpression enhanced centrosome amplification in Her2+ breast cancer cells silenced for E2F3, revealing a role for the E2F activators in maintaining centrosome amplification in part through Nek2. © 2014, American Society for Microbiology.