Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation

• DOI: 10.1073/pnas.94.7.3330
• Publication Date: 2002-07-26T14:43:20Z
• Authors: Francine-Marie Mi...; Sophie Chappuis; Bernard Caillou; Andrea Pasini; Monique Talbot; Roger Monier; Gilbert M. Lenoir; Jean Feunteun; Marc Billaud
• Keywords: 0303 health sciences; Calcitonin Gene-Related Peptide; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases; Mice, Transgenic; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Mice, Inbred DBA; Carcinoma, Medullary; Proto-Oncogene Proteins; Multiple Endocrine Neoplasia Type 1; Animals; Drosophila Proteins; Thyroid Neoplasms

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome that comprises three clinical subtypes: MEN type 2A (MEN-2A), MEN type 2B (MEN-2B), and familial medullary thyroid carcinoma (FMTC). Medullary thyroid carcinoma (MTC), a malignant tumor arising from calcitonin-secreting thyroid C cells, is the cardinal disease feature of this syndrome, and mortality in affected MEN-2 patients is mainly caused by this malignancy. Germ-line mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, are responsible for these three neoplastic-prone disorders. MEN2 mutations convert the RET protooncogene in a dominantly acting oncogene as a consequence of the ligand-independent activation of the tyrosine kinase. The majority of MEN2A and FMTC mutations are located in the extracellular domain and cause the replacement of one of five juxtamembrane cysteines by a different 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 targeted in C cells by placing the transgene under the control of the calcitonin gene-related peptide/calcitonin promoter. Animals of three independent transgenic mouse lines, which expressed the transgene in the 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 to human MTC which afflicts MEN- 2 individuals. These findings provide evidence that the MEN2A mutant form of RET is oncogenic in parafollicular C cells and suggest that these transgenic mice should prove a valuable animal model for hereditary MTC.