title: Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis.
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.
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Miyoung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA 30303, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Oprea-Ilies
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Department of Basic Sciences, Pharmacology Division, Ponce Health Sciences University, Ponce Research Institute, Ponce, P.R. 00716-2348, USA.
authors.forename: Harold I
authors.initials: HI
authors.lastname: Saavedra
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050699:E2F3 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005838:Genotype; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D008938:Mitosis; D000072379:NIMA-Related Kinases; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D050699:E2F3 Transcription Factor; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C098319:E2F3 protein, human; C508053:ERBB2 protein, human; C089441:NEK2 protein, human
keywords: E2F3; Her2+ breast cancer; centrosome amplification; mitosis; xenograft mammary tumor model