MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture.
Expression of immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling proteins is normally restricted to hematopoietic tissues. The basal activity of ITAM-containing proteins is mediated through negative regulation by coreceptors restricted to hematopoietic tissues. We have identified an ITAM signaling domain encoded within the env gene of murine mammary tumor virus (MMTV). Three-dimensional structures derived in vitro from murine cells stably transfected with MMTV env display a depolarized morphology in comparison with control mammary epithelial cells. This effect is abolished by Y>F substitution within the Env ITAM, as well as inhibitors of Syk and Src protein tyrosine kinases. Env-expressing cells bear hallmarks of cell transformation such as sensitivity to apoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or TNFalpha, as well as down-regulation of E-cadherin and Keratin-18. Human normal mammary epithelial cells expressing MMTV Env also develop transformed phenotype, as typified by growth in soft agar and Matrigel invasion. These disruptions are abrogated by Y>F substitutions. We conclude that ITAM-dependent signals are generated through MMTV Env and trigger early hallmarks of transformation of mouse and human mammary epithelial cells. Therefore, these data suggest a heretofore unappreciated potential mechanism for the initiation of breast cancer and identify MMTV Env and ITAM-containing proteins in human breast tumors as probable oncoproteins.
Katz
Elad
E
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lareef
Mohamed H
MH
Rassa
John C
JC
Grande
Shannon M
SM
King
Leslie B
LB
Russo
Jose
J
Ross
Susan R
SR
Monroe
John G
JG
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D002472:Cell Transformation, Viral; D004792:Enzyme Precursors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D015752:Genes, env; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases