title: The E2F transcription factors regulate tumor development and metastasis in a mouse model of metastatic breast cancer.
abstract: While 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.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Hollern
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Honeysett
authors.affiliation: Department of Pathology and Laboratory Medicine, UC Davis, Davis, California, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan, USA andrech1@msu.edu.
authors.forename: Eran R
authors.initials: ER
authors.lastname: Andrechek
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming; D050684:E2F Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050703:E2F2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050699:E2F3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology / Q000556:secondary; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D018345:Mice, Knockout; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D012192:Retroviridae Infections / Q000209:etiology / Q000473:pathology; D015398:Signal Transduction; D059016:Tumor Microenvironment; D014412:Tumor Virus Infections / Q000209:etiology / Q000473:pathology
chemical_list: D000952:Antigens, Polyomavirus Transforming; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; C493754:E2f1 protein, mouse; C484940:E2f2 protein, mouse; C490840:E2f3 protein, mouse