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Gene Expression in RET/PTC3 and E7 Transgenic Mouse Thyroids: RET/PTC3 But Not E7 Tumors Are Partial and Transient Models of Human Papillary Thyroid Cancers

Institute of Interdisciplinary Research (A.B., L.J., V.D., N.D., J.-C.G., J.E.D., F.M., B.C.), School of Medicine, and Department of Endocrinology (B.C.), Erasme University Hospital, Université Libre de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium; Dipartimento di Biologia e Patologia Cellulare e Molecolare (M.S.), Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, G. Salvatore, Università Federico II, 80131 Naples, Italy; Kimmel Center Institute (J.R.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and Inflammation Research (J.R.), Amgen, Inc., Seattle, Washington 98119

Address all correspondence and requests for reprints to: Agnès Burniat, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Campus Erasme, Bat. C, Room C.4.145, Route de Lennik 808, 1070 Brussels, Belgium. E-mail: aburniat{at}ulb.ac.be.

We studied gene expression profiles in two mouse models of human thyroid carcinoma: the Tg-RET/PTC3 (RP3) and Tg-E7 mice. RP3 fusion gene is the most frequent mutation found in the first wave post-Chernobyl papillary thyroid cancers (PTCs). E7 is an oncoprotein derived from the human papillomavirus 16 responsible for most cervical carcinoma in women. Both transgenic mice develop thyroid hyperplasia followed by solid differentiated carcinoma in older animals. To understand the different steps leading to carcinoma, we analyzed thyroid gene expression in both strains at different ages by microarray technology. Important biological processes were differentially regulated in the two tumor types. In E7 thyroids, cell cycle was the most up-regulated process, an observation consistent with the huge size of these tumors. In RP3 thyroids, contrary to E7 tumors, several human PTC characteristics were observed: overexpression of many immune-related genes, regulation of human PTC markers, up-regulation of EGF-like growth factors and significant regulation of angiogenesis and extracellular matrix remodeling-related genes. However, similarities were incomplete; they did not concern the overall gene expression and were not conserved in old animals. Therefore, RP3 tumors are partial and transient models of human PTC. They constitute a good model, especially in young animals, to study the respective role of the biological processes shared with human PTC and will allow testing drugs targeting these validated variables.

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