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A mammary epithelial cell becomes transformed (bottom) after transfection with MMTV envelope protein.
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A conserved activation motif identified in the envelope (Env) protein of murine mammary tumor virus (MMTV) can drive transformation of mammary epithelial cells, according to Katz et al. on page 431. The ability of this motif to transform cells single-handedly suggests that viral infection may be an important and previously unrecognized trigger for breast cancer.
The motif in question is the immunoreceptor tyrosine kinase–activating motif (ITAM). These conserved motifs are usually found in immune cells and, when phosphorylated, serve as docking sites for the assembly of proteins that signal the activation and differentiation of the cell. They have also been found in proteins from some oncogenic viruses such as Epstein Barr virus and Kaposi's sarcoma virus, but what role these motifs play in the transformation process has remained unexplored.
Katz and colleagues now uncover an ITAM motif in the Env protein of MMTV and show that expression of Env in mammary epithelial cells transforms them. The ITAM motif was the key to transformation, as replacement of the conserved tyrosine residues in the motif or inhibition of the kinases that phosphorylate these residues stripped the Env protein of its oncogenic potential.
This study puts the spotlight on a potential new mechanism for MMTV-induced epithelial cell transformation, which has largely been attributed to positional effects—integration of proviral DNA into locations that trigger the expression of cancer-causing host genes. An intriguing wrinkle to this study is the presence of sequences highly homologous to MMTV envelope protein—with intact ITAM motifs—in the DNA of as many as 40% of human breast tumors, although a human homologue of MMTV has yet to be found.
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