Prediction and Genetic Demonstration of a Role for Activator E2Fs in Myc-Induced Tumors

Fujiwara, Kazue; Yuwanita, Inez; Hollern, Daniel P.; Andrechek, Eran R.

doi:10.1158/0008-5472.can-10-2386

Cited by 50 publications

(57 citation statements)

References 32 publications

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“…While exploring the role of E2F1 in tumor development, we found that loss of E2F1 enhanced ductal transformation and accelerated tumor onset. In a previous study of Myc-mediated tumorigenesis, we noted a similar acceleration of tumor onset with loss of E2F1 (19). In agreement with the role of E2F1 in Myc-induced apoptosis (43), we noted that loss of E2F1 reduced the level of apoptosis and caused Myc tumors to grow more quickly.…”

Section: Discussionsupporting

confidence: 88%

“…Similarly, in prostate cancer, patients with detectable nuclear staining for E2F3 had worse prognoses than patients for whom E2F3 was undetectable (27). Furthermore, we demonstrated recently that E2Fs also play a role in relapse-free survival time in human breast cancer (19). Together, these prior studies and was imaged using a goat anti-rabbit secondary antibody (product no.…”

mentioning

confidence: 73%

“…As a predictive tool, genetic signatures allow the identification of signaling pathways that may contribute to tumor development. Indeed, the application of genomic signatures to Myc-induced tumors revealed that E2F transcription factors (E2Fs) were predicted to function in tumorigenesis, and a genetic test of this prediction demonstrated that E2Fs were involved in tumor onset and progression (19). Using a similar approach, the current study predicted a role for the activator E2F transcription factors in MMTV-PyMT-induced tumorigenesis.…”

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confidence: 81%

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The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Hollern

Honeysett

Cardiff

et al. 2014

Molecular and Cellular Biology

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112

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bWhile the E2F transcription factors (E2Fs) have a clearly defined role in cell cycle control, recent work has uncovered new functions. Using genomic signature methods, we predicted a role for the activator E2F transcription factors in the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) mouse model of metastatic breast cancer. To genetically test the hypothesis that the E2Fs function to regulate tumor development and metastasis, we interbred MMTV-PyMT mice with E2F1, E2F2, or E2F3 knockout mice. With the ablation of individual E2Fs, we noted alterations of tumor latency, histology, and vasculature. Interestingly, we noted striking reductions in metastatic capacity and in the number of circulating tumor cells in both the E2F1 and E2F2 knockout backgrounds. Investigating E2F target genes that mediate metastasis, we found that E2F loss led to decreased levels of vascular endothelial growth factor (Vegfa), Bmp4, Cyr61, Nupr1, Plod 2, P4ha1, Adamts1, Lgals3, and Angpt2. These gene expression changes indicate that the E2Fs control the expression of genes critical to angiogenesis, the remodeling of the extracellular matrix, tumor cell survival, and tumor cell interactions with vascular endothelial cells that facilitate metastasis to the lungs. Taken together, these results reveal that the E2F transcription factors play key roles in mediating tumor development and metastasis in addition to their well-characterized roles in cell cycle control. Breast cancer remains a leading cause of death for women, with high mortality rates attributed to distant metastasis (1). To simplify the examination of signaling pathway requirements in metastatic breast cancer, research has turned to mouse model systems. Previous studies with mouse models of breast cancer have begun to reveal the mechanistic features of breast cancer metastasis, and in vivo selection has demonstrated the ability to select for tumors that metastasize to a specific location (2-5). Yet we lack a complete understanding of the pathways that govern the molecular circuitry of metastatic breast cancer. One model that has been integral in examining metastatic progression is the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) model. Originally described as exhibiting rapid tumor onset and a high degree of pulmonary metastasis (6), this model has since been used to examine a number of facets of metastasis. For example, work using the MMTV-PyMT model led to the discovery of the prometastatic signaling exchange between tumors and macrophages (7). In addition, the metastatic contributions of individual signaling molecules, such as transforming growth factor ␤ (TGF-␤), AKT, and adiponectin, have also been uncovered using this model (8-10). Given that PyMT can activate multiple signaling pathways with relevance to human breast cancer (11), there is clear utility in this model for characterizing pathways that contribute to breast cancer metastasis.The identification of signaling pathways contributing to tumor progression has bee...

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Section: Discussionsupporting

confidence: 88%

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confidence: 73%

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confidence: 81%

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The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Hollern

Honeysett

Cardiff

et al. 2014

Molecular and Cellular Biology

Self Cite

112

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“…E2F2 has a strong ability to promote cell cycle progression (27), and aberrant expression of E2F2 can lead to abnormal cellular proliferation. Upregulation of E2F2 has been reported in prostate (28), breast cancer (29) and astrocytoma (30). Our data on OS cells are consistent with those from previous studies reporting that the upregulation of E2F2 may contribute to cell malignancy.…”

Section: Discussionmentioning

confidence: 99%

Tumor-suppressive microRNA-let-7a inhibits cell proliferation via targeting of E2F2 in osteosarcoma cells

Iwasaki

Tanaka

Kawano

et al. 2015

International Journal of Oncology

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Abstract. MicroRNAs (miRNAs) regulate cell proliferation and differentiation by silencing gene expression at the post-transcriptional level; moreover, by binding to the complementary sequences within mRNAs in cancer cells, these small non-coding RNA molecules can function as tumor suppressors or oncogenes. Recently, the dysregulation of miRNA expression has been found to be associated with increased tumorigenicity and poor prognosis in several cancer types, including osteosarcoma (OS). To identify potential oncogenic factors in OS, we analyzed changes in the expression profile of miRNAs and its downstream mRNAs in five OS cell lines and human mesenchymal stem cells (hMSCs) by a microarray-based approach. The expression of an miRNA-let-7a was significantly downregulated and E2F2 was significantly upregulated in all tested OS cells compared with hMSCs. When let-7a was transfected into OS cell lines, the expression of E2F2 in the cells was greatly suppressed, suggesting that E2F2 is a target of miRNA-let-7a in OS cells. The transfection of let-7a further inhibited cell cycle progression and proliferation of OS cells. In addition, let-7a overexpression in OS cells significantly suppressed the tumor growth in vivo. The present study demonstrates the novel mechanism that regulates E2F2 expression via miRNA-let-7a in OS cells. Because E2F2 is pivotal in promoting cell growth through the regulation of several genes, our results might facilitate the development of new therapeutic targets for the treatment of OS.

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“…In addition, breast cancer cells with molecular alterations affecting the Rb pathway or E2F overexpression display altered chemotherapeutic responses (32)(33)(34)(35)(36), including resistance to the Cdk4/Cdk6 inhibitor PD-0332991 (37,38). Mouse models demonstrated the requirement for E2Fs in mammary carcinogenesis, since ablation of E2F1 and E2F3 suppressed Her2/Neu and Myc-induced mammary tumorigenesis (26,39,40). Thus, studying E2F functions may provide clues not only to understanding how mammary tumors initiate and progress but also to how breast cancer cells fail to respond to common therapies.…”

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confidence: 99%

E2F Activators Signal and Maintain Centrosome Amplification in Breast Cancer Cells

Lee

Moreno

Saavedra

2014

Molecular and Cellular Biology

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bCentrosomes 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.

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Prediction and Genetic Demonstration of a Role for Activator E2Fs in Myc-Induced Tumors

Cited by 50 publications

References 32 publications

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Tumor-suppressive microRNA-let-7a inhibits cell proliferation via targeting of E2F2 in osteosarcoma cells

E2F Activators Signal and Maintain Centrosome Amplification in Breast Cancer Cells

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