title: Increased metastasis with loss of E2F2 in Myc-driven tumors.
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.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
authors.forename: Inez
authors.initials: I
authors.lastname: Yuwanita
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Barnes
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Monterey
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: O'Reilly
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI48824, Michigan, USA.
authors.forename: Eran R
authors.initials: ER
authors.lastname: Andrechek
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement; D004195:Disease Models, Animal; D050703:E2F2 Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D016259:Genes, myc; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D061986:MCF-7 Cells; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D060066:Protein Interaction Maps; D034622:RNA Interference; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; C484940:E2f2 protein, mouse; C090899:PTPRD protein, human; C490395:Ptprd protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: E2F transcription factors; MMTV-Myc; PTPRD; gene expression; metastasis