Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice Journal Article
| Authors: | Franco, A. T.; Malaguarnera, R.; Refetoff, S.; Liao, X. H.; Lundsmith, E.; Kimura, S.; Pritchard, C.; Marais, R.; Davies, T. F.; Weinstein, L. S.; Chen, M.; Rosen, N.; Ghossein, R.; Knauf, J. A.; Fagin, J. A. |
| Article Title: | Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice |
| 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. |
| Keywords: | immunohistochemistry; signal transduction; protein expression; disease course; nonhuman; cancer incidence; ki-67 antigen; mouse; phenotype; animals; mice; mice, knockout; gene expression; animal experiment; animal model; carcinogenesis; mice, transgenic; cancer invasion; reverse transcriptase polymerase chain reaction; cell transformation; gene control; thyroid neoplasms; hypothyroidism; tumor growth; thyroid gland; b raf kinase; thyroid tumor; ras; proto-oncogene proteins b-raf; thyrotropin; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; g protein; thyroid follicular carcinoma; thyroxine; thyrotropin blood level; radioimmunoassay; pax8; thyrotropin receptor; thyroid hormone metabolism; iodide peroxidase; receptors, thyrotropin |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 108 |
| Issue: | 4 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2011-01-25 |
| Start Page: | 1615 |
| End Page: | 1620 |
| Language: | English |
| DOI: | 10.1073/pnas.1015557108 |
| PUBMED: | 21220306 |
| PROVIDER: | scopus |
| PMCID: | PMC3029699 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 23 June 2011" - "CODEN: PNASA" - "Source: Scopus" |
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