Oncotarget

Research Papers:

Increased metastasis with loss of E2F2 in Myc-driven tumors

Inez Yuwanita _, Danielle Barnes, Michael D. Monterey, Sandra O’Reilly, Eran R. Andrechek

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Oncotarget. 2015; 6:38210-38224. https://doi.org/10.18632/oncotarget.5690

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Abstract

Inez Yuwanita1, Danielle Barnes1, Michael D. Monterey1, Sandra O'Reilly1, Eran R. Andrechek1

1Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA

Correspondence to:

Eran R. Andrechek, e-mail: andrech1@msu.edu

Keywords: MMTV-Myc, metastasis, E2F transcription factors, PTPRD, gene expression

Received: June 01, 2015     Accepted: September 30, 2015     Published: October 13, 2015

ABSTRACT

In human breast cancer, mortality is associated with metastasis to distant sites. Therefore, it is critical to elucidate the biological mechanisms that underlie tumor progression and metastasis. Using signaling pathway signatures we previously predicted a role for E2F transcription factors in Myc induced tumors. To test this role we interbred MMTV-Myc transgenic mice with E2F knockouts. Surprisingly, we observed that the loss of E2F2 sharply increased the percentage of lung metastasis in MMTV-Myc transgenic mice. Examining the gene expression profile from these tumors, we identified genetic components that were potentially involved in mediating metastasis. These genes were filtered to uncover the genes involved in metastasis that also impacted distant metastasis free survival in human breast cancer. In order to elucidate the mechanism by which E2F2 loss enhanced metastasis we generated knockdowns of E2F2 in MDA-MB-231 cells and observed increased migration in vitro and increased lung colonization in vivo. We then examined genes that were differentially regulated between tumors from MMTV-Myc, MMTV-Myc E2F2−/−, and lung metastases samples and identified PTPRD. To test the role of PTPRD in E2F2-mediated breast cancer metastasis, we generated a knockdown of PTPRD in MDA-MB-231 cells. We noted that decreased levels of PTPRD resulted in decreased migration in vitro and decreased lung colonization in vivo. Taken together, these data indicate that E2F2 loss results in increased metastasis in breast cancer, potentially functioning through a PTPRD dependent mechanism.

Author Information

Inez Yuwanita
Primary Contact  _

Danielle Barnes

Michael D. Monterey

Sandra O’Reilly

Eran R. Andrechek


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