Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

Aime T. Franco, Roberta Malaguarnera, Samuel Refetoff, Xiao Hui Liao, Emma Lundsmith, Shioko Kimura, Catrin Pritchard, Richard Marais, Terry F. Davies, Lee S. Weinstein, Min Chen, Neal Rosen, Ronald Ghossein, Jeffrey A. Knauf, James A. Fagin

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

Mutations of BRAF are found in ∼45% of papillary thyroid cancers and are enriched in tumors with more aggressive properties. We developed mice with a thyroid-specific knock-in of oncogenic Braf (LSL-BrafV600E/TPO-Cre) to explore the role of endogenous expression of this oncoprotein on tumor initiation and progression. In contrast to other Braf-induced mouse models of tumorigenesis (i.e., melanomas and lung), in which knock-in of Braf V600E induces mostly benign lesions, Braf-expressing thyrocytes become transformed and progress to invasive carcinomas with a very short latency, a process that is dampened by treatment with an allosteric MEK inhibitor. These mice also become profoundly hypothyroid due to deregulation of genes involved in thyroid hormone biosynthesis and consequently have high TSH levels. To determine whether TSH signaling cooperates with oncogenic Braf in this process, we first crossed LSL-BrafV600E/TPO-Cre with TshR knockout mice. Although oncogenic Braf was appropriately activated in thyroid follicular cells of these mice, they had a lower mitotic index and were not transformed. Thyroid-specific deletion of the Gsα gene in LSL-Braf V600E/TPO-Cre/Gnas-E1fl/fl mice also resulted in an attenuated cancer phenotype, indicating that the cooperation of TshR with oncogenic Braf is mediated in part by cAMP signaling. Once tumors were established in mice with wild-type TshR, suppression of TSH did not revert the phenotype. These data demonstrate the key role of TSH signaling in Braf-induced papillary thyroid cancer initiation and provide experimental support for recent observations in humans pointing to a strong association between TSH levels and thyroid cancer incidence.

Original languageEnglish
Pages (from-to)1615-1620
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number4
DOIs
StatePublished - 25 Jan 2011

Keywords

  • G protein
  • Pax8
  • Ras

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