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Journal of Virology, September 2006, p. 9000-9008, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00788-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

An Immunoreceptor Tyrosine Activation Motif in the Mouse Mammary Tumor Virus Envelope Protein Plays a Role in Virus-Induced Mammary Tumors

Susan R. Ross,^1,3* John W. Schmidt,^1,3 Elad Katz,^2,3 Laura Cappelli,^1,3 Stacy Hultine,^1,3 Phyllis Gimotty,^3,4 and John G. Monroe^2,3

Department of Microbiology,¹ Department of Pathology and Laboratory Medicine,² Abramson Family Cancer Center,³ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104⁴

Received 18 April 2006/ Accepted 22 June 2006

Mouse mammary tumor virus (MMTV) induces breast cancer with almost 100% efficiency in susceptible strains through insertional activation of protooncogenes, such as members of the wnt and fibroblast growth factor (fgf) families. We previously showed that expression of the MMTV envelope protein (Env) in normal immortalized mammary epithelial cells grown in three-dimensional cultures caused their morphological transformation, and that this phenotype depended on an immunoreceptor tyrosine-based activation motif (ITAM) present in Env and signaling through the Syk tyrosine kinase (E. Katz, M. H. Lareef, J. C. Rassa, S. M. Grande, L. B. King, J. Russo, S. R. Ross, and J. G. Monroe, J. Exp. Med. 201:431-439, 2005). Here, we examined the role of the Env protein in virus-induced mammary tumorigenesis in vivo. Similar to the effect seen in vitro, Env expression in the mammary glands of transgenic mice bearing either full-length wild-type provirus or only Env transgenes showed increased lobuloalveolar budding. Introduction of the ITAM mutation into the env of an infectious, replication-competent MMTV or into MMTV/murine leukemia virus pseudotypes had no effect on incorporation of Env into virus particles or on in vitro infectivity. Moreover, replication-competent MMTV bearing the ITAM mutation in Env infected lymphoid and mammary tissue at the same level as wild-type MMTV and was transmitted through milk. However, mammary tumor induction was greatly attenuated, and the pattern of oncogene activation was altered. Taken together, these studies indicate that the MMTV Env protein participates in mammary epithelial cell transformation in vivo and that this requires a functional ITAM in the envelope protein.

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* Corresponding author. Mailing address: University of Pennsylvania, 313BRBII/III, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-9764. Fax: (215) 573-2028. E-mail: rosss{at}mail.med.upenn.edu.

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Journal of Virology, September 2006, p. 9000-9008, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00788-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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