Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis

• Type of Material: Article
• Authors: Miyoung Lee, Emory University; Gabriela Oprea, Emory University; Harold Saavedra, Emory University
• Language: English
• Date: 2015-11-10
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Lee et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.5686
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Start Page: 37316
• End Page: 37334
• Grant/Funding Information: This research project was supported by R01 CA151521 and U54CA163071 from the National Institutes of Health. The project described was also supported by Award Number G12MD007579 from the National Institute on Minority Health and Health Disparities.
• Keywords: E2F3; mitosis; centrosome amplification; xenograft mammary tumor model; Her2+ breast cancer
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

The E2F transcriptional activators E2F1, E2F2 and E2F3a regulate many important cellular processes, including DNA replication, apoptosis and centrosome duplication. Previously, we demonstrated that silencing E2F1 or E2F3 suppresses centrosome amplification (CA) and chromosome instability (CIN) in Her2+ breast cancer cells without markedly altering proliferation. However, it is unknown whether and how silencing a single E2F activator, E2F3, affects malignancy of human breast cancer cells. Thus, we injected HCC1954 Her2+ breast cancer cells silenced for E2F3 into mammary fat pads of immunodeficient mice and demonstrated that loss of E2F3 retards tumor growth. Surprisingly, silencing of E2F3 led to significant reductions in mitotic indices relative to vector controls, while the percentage of cells undergoing S phase were not affected. Nek2 is a mitotic kinase commonly upregulated in breast cancers and a critical regulator of Cdk4- or E2F- mediated CA. In this report, we found that Nek2 overexpression rescued back the CA caused by silencing of shE2F3. However, the effects of Nek2 overexpression in affecting tumor growth rates of shE2F3 and shE2F3; GFP cells were inconclusive. Taken together, our results indicate that E2F3 silencing decreases mammary tumor growth by reducing percentage of cells undergoing mitosis.