title: Novel common integration sites targeted by mouse mammary tumor virus insertion in mammary tumors have oncogenic activity.
abstract: Non-acute transforming retroviruses like mouse mammary tumor virus (MMTV) cause cancer, at least in part, through integration near cellular genes involved in growth control, thereby de-regulating their expression. It is well-established that MMTV commonly integrates near and activates expression of members of the Wnt and Fgf pathways in mammary tumors. However, there are a significant number of tumors for which the proviral integration sites have not been identified. Here, we used high through-put screening to identify common integration sites (CISs) in MMTV-induced tumors from C3H/HeN and BALB/c mice. As expected, members of both the Wnt and Fgf families were identified in this screen. In addition, a number of novel CISs were found, including Tcf7l2, Antxr1/Tem8, and Arhgap18. We show here that expression of these three putative oncogenes in normal murine mammary gland cells altered their growth kinetics and caused their morphological transformation when grown in three dimensional cultures. Additionally, expression of Tcf7l2 and Antxr1/Tem8 sensitized cells to exogenous WNT ligand. As Tcf7l2, Antxr1/Tem8, and Arhgap18 have been associated with human breast and other cancers, these data demonstrate that MMTV-induced insertional mutation remains an important means for identifying genes involved in breast cancer.
authors.affiliation: Department of Microbiology/Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hyoung H
authors.initials: HH
authors.lastname: Kim
authors.forename: A Pieter J
authors.initials: AP
authors.lastname: van den Heuvel
authors.forename: John W
authors.initials: JW
authors.lastname: Schmidt
authors.forename: Susan R
authors.initials: SR
authors.lastname: Ross
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D049109:Cell Proliferation; D048430:Cell Shape; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D051538:Hepatocyte Nuclear Factor 1-alpha; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000821:virology*; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology*; D051379:Mice; D008840:Microfilament Proteins; D016254:Mutagenesis, Insertional; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000235:genetics; D051822:T Cell Transcription Factor 1 / Q000235:genetics; D014407:Tumor Cells, Cultured; D016662:Virus Integration
chemical_list: C523012:Antxr1 protein, mouse; D014408:Biomarkers, Tumor; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D008840:Microfilament Proteins; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; D051822:T Cell Transcription Factor 1
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