The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium.
Genetic analysis of human papillary thyroid carcinomas (PTC) has revealed unique chromosomal translocations that form oncogenic fusion proteins and promote thyroid tumorigenesis in up to 60% of tumors examined. Although, the majority of thyroid specific translocations involve the growth factor receptor c-RET, variant rearrangements of the receptor for nerve growth factor, NTRK1 have also been described. One such translocation, TRK-T1, forms a fusion protein composed of the carboxyl terminal tyrosine kinase domain of NTRK1 and the amino terminal portion of TPR (Translocated Promoter Region). To determine if TRK-T1 expression can cause thyroid cancer in vivo, we developed transgenic mice that express the human TRK-T1 fusion protein in the thyroid. Immunohistochemical analysis of TRK-T1 transgenic mouse thyroids revealed TRK-T1 staining within the thyroid follicular epithelium. In contrast to nontransgenic littermates, 54% of transgenic mice developed thyroid abnormalities that included follicular hyperplasia and papillary carcinoma. Furthermore, all transgenic mice examined greater than 7 months of age developed thyroid hyperplasia and/or carcinoma. These data support the conclusion that TRK-T1 is oncogenic in vivo and contributes to the neoplastic transformation of the thyroid.
Russell
J P
JP
Department of Otolaryngology, Head & Neck Surgery, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Powell
D J
DJ
Cunnane
M
M
Greco
A
A
Portella
G
G
Santoro
M
M
Fusco
A
A
Rothstein
J L
JL
D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism; D002417:Cattle; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D011519:Proto-Oncogenes; D051381:Rats; D011916:Rats, Inbred F344; D020917:Receptor, trkA / Q000096:biosynthesis / Q000235:genetics*; D013954:Thyroglobulin / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D014178:Translocation, Genetic
D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C073597:TPR protein, human; D013954:Thyroglobulin; D020917:Receptor, trkA