The E2F activators control multiple mitotic regulators and maintain genomic integrity through Sgo1 and BubR1

• Type of Material: Article
• Authors: Miyoung Lee, Emory University; Yainyrette Rivera-Rivera, Ponce Health Sciences University; Carlos Moreno, Emory University; Harold Saavedra, Emory University
• Language: English
• Date: 2017-09-29
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Lee et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.20765
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 8
• Issue: 44
• Start Page: 77649
• End Page: 77672
• Grant/Funding Information: The project was also supported by 2U54MD007587 from the PRCTRC, G12MD007579 from RCMI, The Puerto Rico Science, Technology and Research Trust, and Ponce Medical School Foundation Inc. under the cooperative agreement 2016-00026.; The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; This research project was supported by R01 CA151521 and PSM-U54-CA163071 and MCC-U54-CA163068 from the National Institutes of Health.
• Keywords: CYCLE PROGRESSION; Science & Technology; Oncology; Cell Biology; breast cancer; centrosome; BREAST-CANCER CELLS; Life Sciences & Biomedicine; PROTEIN PHOSPHATASE 2A; chromosome instability; CHROMOSOMAL INSTABILITY; CENTROSOME AMPLIFICATION; S-PHASE ENTRY; TRANSCRIPTION FACTORS; KINASE INHIBITORS; transcription factors; TUMOR-FORMATION; mammary epithelial cells; DNA-REPLICATION
• Research Categories: Health Sciences, Pathology; Health Sciences, Pharmacology; Biology, Genetics

Abstract

The E2F1, E2F2, and E2F3a transcriptional activators control proliferation. However, how the E2F activators regulate mitosis to maintain genomic integrity is unclear. Centrosome amplification (CA) and unregulated spindle assembly checkpoint (SAC) are major generators of aneuploidy and chromosome instability (CIN) in cancer. Previously, we showed that overexpression of single E2F activators induced CA and CIN in mammary epithelial cells, and here we show that combined overexpression of E2F activators did not enhance CA. Instead, the E2F activators elevated expression of multiple mitotic regulators, including Sgo1, Nek2, Hec1, BubR1, and Mps1/TTK. cBioPortal analyses of the TCGA database showed that E2F overexpression in lobular invasive breast tumors correlates with overexpression of multiple regulators of chromosome segregation, centrosome homeostasis, and the SAC. Kaplan-Meier plots identified correlations between individual or combined overexpression of E2F1, E2F3a, Mps1/TTK, Nek2, BubR1, or Hec1 and poor overall and relapse-free survival of breast cancer patients. In MCF10A normal mammary epithelial cells cooverexpressing E2Fs, transient Sgo1 knockdown induced CA, high percentages of premature sister chromatid separation, chromosome losses, increased apoptosis, and decreased cell clonogenicity. BubR1 silencing resulted in chromosome losses without CA, demonstrating that Sgo1 and BubR1 maintain genomic integrity through two distinct mechanisms. Our results suggest that deregulated activation of the E2Fs in mammary epithelial cells is counteracted by activation of a Sgo1-dependent mitotic checkpoint.