Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis.
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.
['Lee|Miyoung|M|', 'Oprea-Ilies|Gabriela|G|', 'Saavedra|Harold I|HI|']
D000818:Animals D001943:Breast Neoplasms D045744:Cell Line, Tumor D049109:Cell Proliferation D050699:E2F3 Transcription Factor 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 D034622:RNA Interference D018719:Receptor, ErbB-2 D015398:Signal Transduction D013997:Time Factors D014162:Transfection D047368:Tumor Burden
E2F3 Her2+ breast cancer mitosis centrosome amplification xenograft mammary tumor model