title: Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models.
abstract: We have adapted the avian leukosis virus RCAS (replication-competent avian sarcoma-leukosis virus LTR splice acceptor)-mediated somatic gene transfer technique to introduce oncogenes into mammary cells in mice transgenic for the avian subgroup A receptor gene, tva, under control of the mouse mammary tumor virus (MMTV) promoter. Intraductal instillation of an RCAS vector carrying the polyoma middle T antigen (PyMT) gene (RCAS-PyMT) induced multiple, oligoclonal tumors within 3 weeks in infected mammary glands of MMTV-tva transgenic mice. The rapid appearance of these tumors from a relatively small pool of infected cells (estimated to be approximately 2 x 10(3) cells per gland by infection with RCAS carrying a GFP gene; RCAS-GFP) was accompanied by a high fraction of cells positive for Ki67, Cyclin D1, and c-Myc, implying strong proliferation competence. Furthermore, the tumors displayed greater cellular heterogeneity than did tumors arising in MMTV-PyMT mice, suggesting that RCAS-PyMT transforms a relatively immature cell type. Infection of mice transgenic for both MMTV-Wnt-1 and MMTV-tva with RCAS virus carrying an activated Neu oncogene dramatically enhanced tumor formation over what is observed in uninfected bitransgenic animals. We conclude that infection of mammary glands with retrovirus vectors is an efficient means to screen candidate oncogenes for their capacity to initiate or promote mammary carcinogenesis in the mouse.
authors.affiliation: Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Du
authors.forename: Katrina
authors.initials: K
authors.lastname: Podsypanina
authors.forename: Shixia
authors.initials: S
authors.lastname: Huang
authors.forename: Amanda
authors.initials: A
authors.lastname: McGrath
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Toneff
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bogoslovskaia
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Moraes
authors.forename: Michele
authors.initials: M
authors.lastname: Fluck
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
authors.forename: Harold E
authors.initials: HE
authors.lastname: Varmus
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D001358:Avian Sarcoma Viruses / Q000235:genetics*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005822:Genetic Vectors / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D009858:Oncogenic Viruses / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D000952:Antigens, Polyomavirus Transforming; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1