DEVELOPMENT OF MEDULLARY-THYROID CARCINOMA IN TRANSGENIC MICE EXPRESSING THE RET PROTOONCOGENE ALTERED BY A MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A MUTATION

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome that comprises three clinical subtypes: MEN type 2A (M EN-2A), MEN type 2B (MEN-2B), and familial medullary thyroid carcinoma (FMTC). Medullary thyroid carcinoma (FMTC), a malignant tumor arising from calcitonin-secreting thyroid C cells, is tile cardinal disease f eature of this syndrome, and mortality in affected MEN-2 patients is m ainly caused by this malignancy, Germ-line mutations of the RET protoo ncogene, which encodes a receptor tyrosine kinase, are responsible for these three neoplastic-prone disorders, MEN2 mutations convert the RE T protooncogene in a dominantly acting oncogene as a consequence of th e ligand-independent activation of the tyrosine kinase. The majority o f MEN2A and FMTC mutations are located in the extracellular domain and cause the replacement of one of five juxtamembrane cysteines by a dif ferent amino acid, To examine whether expression of a MEN2A allele of RET results in transformation of C cells, we have used the transgenic approach, Expression of the RET gene altered by a MEN2A mutation was t argeted in C tells by placing the transgene under the control of the c alcitonin gene-related peptide/calcitonin promoter. Animals of three I ndependent transgenic mouse lines, which expressed the transgene In th e thyroid, displayed overt bilateral C cell hyperplasia as early as 3 weeks of age and subsequently developed multifocal and bilateral MTC. Moreover, these tumors were morphologically and biologically similar t o human MTC which afflicts MEN2 individuals, These findings provide ev idence that the MEN2A mutant form of RET is oncogenic in parafollicula r C cells and suggest that these transgenic mice should prove a valuab le animal model for hereditary MTC.