Differentiated carcinomas develop as a consequence of the thyroid specific expression of a thyroglobulin-human...

The oncogenic properties of the high risk human papillomaviruses (HPV) E7 protein are attributed to its interaction with the retinoblastoma susceptibility gene product RB1 and other related proteins. We report here the generation of a transgenic model expressing the E7 oncogene of HPV16 in thyroid follicular cells, under control of the bovine thyroglobulin gene promoter. Transgenics develop differentiated and functionally regulated thyroid goitres, due to thyroid cell proliferation and accumulation of colloid. On the background of this colloid goitre, the mice develop foci of more actively proliferating cells that become invasive and ultimately tend to loose their differentiation. Old mice display secondary tumour nodules that mimic the various histological aspects of the human differentiated thyroid cancers: the follicular and papillary carcinomas. The development of totally undifferentiated carcinoma is in contrast exceptional. We conclude that RB1, and/or related proteins, are responsible for the strict negative control of proliferation that characterizes the thyroid cell of the adult. Inactivation of these proteins results in a continuous growth of the thyroid, without affecting its differentiation, function and regulation. Given the high frequency of progression to highly malignant phenotypes, the retinoblastoma susceptibility and related genes are good candidates as targets for mutations or deletions in early steps of human thyroid carcinogenesis. The search for such mutations in human thyroid cancers will test if this hypothesis holds true.