Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation

Germ line mutations of the RET proto-oncogene are responsible for the devel opment of multiple endocrine neoplasia type 2A (MEN 2A), an inherited cance r syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia, To study the mechanism of tissue-specific tumo r development by RET with a MEN2A (cysteine 634-->arginine) mutation, we ge nerated transgenic mice by introducing the RET-MEN2A gene fused to Moloney murine leukemia virus long terminal repeat. Expression of the transgene and its product was detected at variable levels in a variety of tissues includ ing thyroid, heart, liver, colon, parotid gland, and brain. All of 29 mice analyzed developed thyroid C-cell hyperplasia or medullary carcinoma, accom panying high levels of serum calcitonin, In addition, development of mammar y or parotid gland adenocarcinoma was observed in one-half of the transgeni c mice. RET dimerization and its complex formation with Shc and Grb2 adapto r proteins were detected in tumor tissues, Unexpectedly, no tumor formation was found in other tissues despite RET-MEN2A expression where RET dimeriza tion was undetectable. Because these tissues but not tumors expressed glial cell line-derived neurotrophic factor family receptor alpha (GFR alpha) at high levels, this suggested that GFR alpha expression may interfere in the dimerization of the RET-MEN2A mutant proteins, leading to tissue-specific tumor development in vivo.