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C-cell and thyroid epithelial tumours and altered follicular development in transgenic mice expressing the long isoform of MEN 2A RET

Oncogene volume 20, pages 3986–3994 (2001)Cite this article

Abstract

Gain-of-function mutations in the gene encoding the receptor tyrosine kinase RET have been identified as the aetiological factor for multiple endocrine neoplasia type 2A (MEN2A). MEN2A is a dominantly-inherited cancer predisposition syndrome characterized by medullary thyroid carcinoma, a tumour of the calcitonin-producing thyroid C-cells. There are three isoforms of RET: RET9, RET43 and RET51, and although in vitro evidence suggests they vary in cellular transformation activities, little is known about their function in tumorigenesis in vivo. To address this, we used RET51 cDNA to construct mice in which the most frequent MEN2A mutation, Cys-634-Arg, was expressed under the control of the human calcitonin promoter (CT-2A mice). These mice developed C-cell tumours resembling human MTC and follicular tumours resembling human papillary thyroid carcinoma (PTC) depending on the founder line examined. One founder line developed compound MTC/PTC at low frequency (8%) and pancreatic cystadenocarcinoma. CT-2A mice also displayed a developmental defect in thyroid follicular structure, in which much of the thyroid was occupied by large irregular cystic follicles thought to be derived from the ultimobranchial body, a developmental precursor of the thyroid gland. The CT-2A mice will provide a suitable model to further study the effects of the MEN 2A RET mutation in vivo.

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Acknowledgements

We wish to thank Sara Peleg for kindly supplying the human calcitonin promoter DNA and Massimo Santoro for the anti-TTF-1 antibody. This work was supported by The Cancer Research Campaign (CRC).

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Author notes

  1. Lucinda Reynolds

    Present address: National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

  2. Darrin P Smith

    Present address: Breakthrough Breast Cancer Research Group, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

Authors and Affiliations

  1. CRC Department of Oncology, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 2XY, UK

    Lucinda Reynolds, Ken Jones, Douglas J Winton, Aaron Cranston, Carol Houghton, Louise Howard, Bruce A J Ponder & Darrin P Smith

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Reynolds, L., Jones, K., Winton, D. et al. C-cell and thyroid epithelial tumours and altered follicular development in transgenic mice expressing the long isoform of MEN 2A RET. Oncogene 20, 3986–3994 (2001). https://doi.org/10.1038/sj.onc.1204434

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