The ultimate target tissue for mouse mammary tumor virus (MMTV) is the mammary gland, where viral integrations near cellular oncogenes result in mammary tumors. MMTV also uses cells of the immune system in its journey from milk to the mammary gland of offspring that nurse on infected mothers. A better understanding of how MMTV infects these different cells and reaches its target tissue is dependent on identifying the cell surface entry receptor. Moreover, although MMTV only infects rodent tissue culture cells, several groups have recently isolated viral sequences highly related to MMTV from human breast cancer but not normal tissue. Thus, a complete understanding of MMTV's cell-type- and species-tropism is critical. Although we previously cloned a receptor for MMTV (MTVR2), we recently discovered by phenotypic screening of the T31mouse/hamster radiation hybrid cell panel that mouse transferrin receptor 1 (TrfR1) is the major cell entry receptor. The goals of this proposal are to determine how MMTV interacts with this well-characterized receptor in infection, both at the level of the cell and the whole animal. The first of the two proposed aims will take advantage of the TrfR1 crystal structure and the availability of known trafficking mutants to determine species-specific tropism and how MMTV uses this receptor for entry into cells.
The second aim will examine in vivo infection in mice that have defects in the TrfR1 gene and in other steps of transferrin/iron metabolism. Together, these two approaches will allow us to better understand how viruses utilize the biology of their host for propagation and how MMTV specifically induces breast cancer in mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073746-09
Application #
7015623
Study Section
Virology Study Section (VR)
Program Officer
Cole, John S
Project Start
1997-05-15
Project End
2007-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
9
Fiscal Year
2006
Total Cost
$270,857
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kim, Hyoung H; Grande, Shannon M; Monroe, John G et al. (2012) Mouse mammary tumor virus suppresses apoptosis of mammary epithelial cells through ITAM-mediated signaling. J Virol 86:13232-40
Okeoma, Chioma M; Huegel, Alyssa L; Lingappa, Jaisri et al. (2010) APOBEC3 proteins expressed in mammary epithelial cells are packaged into retroviruses and can restrict transmission of milk-borne virions. Cell Host Microbe 8:534-43
Wang, Enxiu; Obeng-Adjei, Nyamekye; Ying, Qihua et al. (2008) Mouse mammary tumor virus uses mouse but not human transferrin receptor 1 to reach a low pH compartment and infect cells. Virology 381:230-40
Ross, Susan R; Schmidt, John W; Katz, Elad et al. (2006) An immunoreceptor tyrosine activation motif in the mouse mammary tumor virus envelope protein plays a role in virus-induced mammary tumors. J Virol 80:9000-8
Wang, Enxiu; Albritton, Lorraine; Ross, Susan R (2006) Identification of the segments of the mouse transferrin receptor 1 required for mouse mammary tumor virus infection. J Biol Chem 281:10243-9
Goedert, J J; Rabkin, C S; Ross, S R (2006) Prevalence of serologic reactivity against four strains of mouse mammary tumour virus among US women with breast cancer. Br J Cancer 94:548-51
Katz, Elad; Lareef, Mohamed H; Rassa, John C et al. (2005) MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. J Exp Med 201:431-9
Burzyn, Dalia; Rassa, John C; Kim, David et al. (2004) Toll-like receptor 4-dependent activation of dendritic cells by a retrovirus. J Virol 78:576-84
Hein, Sibyll; Prassolov, Vladimir; Zhang, Yuanming et al. (2003) Sodium-dependent myo-inositol transporter 1 is a cellular receptor for Mus cervicolor M813 murine leukemia virus. J Virol 77:5926-32
Zhang, Yuanming; Rassa, John C; deObaldia, Maria Elena et al. (2003) Identification of the receptor binding domain of the mouse mammary tumor virus envelope protein. J Virol 77:10468-78

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