Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation
Abstract
The BRAFT1799A mutation is the most common genetic alteration in papillary thyroid carcinomas (PTC). It is also found in a subset of papillary microcarcinomas, consistent with a role in tumor initiation. PTCs with BRAFT1799A are often invasive and present at a more advanced stage. BRAFT1799A is found with high prevalence in tall-cell variant PTCs and in poorly differentiated and undifferentiated carcinomas arising from PTCs. To explore the role of BRAFV600E in thyroid cancer pathogenesis, we targeted its expression to thyroid cells of transgenic FVB/N mice with a bovine thyroglobulin promoter. Two Tg-BRAFV600E lines (Tg-BRAF2 and Tg-BRAF3) were propagated for detailed analysis. Tg-BRAF2 and Tg-BRAF3 mice had increased thyroid-stimulating hormone levels (>7- and ∼2-fold, respectively). This likely resulted from decreased expression of thyroid peroxidase, sodium iodine symporter, and thyroglobulin. All lines seemed to successfully compensate for thyroid dysfunction, as serum thyroxine/triiodothyronine and somatic growth were normal. Thyroid glands of transgenic mice were markedly enlarged by 5 weeks of age. In Tg-BRAF2 mice, PTCs were present at 12 and 22 weeks in 14 of 15 and 13 of 14 animals, respectively, with 83% exhibiting tall-cell features, 83% areas of invasion, and 48% foci of poorly differentiated carcinoma. Tg-BRAF3 mice also developed PTCs, albeit with lower prevalence (3 of 12 and 4 of 9 at 12 and 22 weeks, respectively). Tg-BRAF2 mice had a 30% decrease in survival at 5 months. In summary, thyroid-specific expression of BRAFV600E induces goiter and invasive PTC, which transitions to poorly differentiated carcinomas. This closely recapitulates the phenotype of BRAF-positive PTCs in humans and supports a key role for this oncogene in its pathogenesis.
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Dedifferentiation and development of radioactive iodine refractory diseases, resulting from decreased thyroid differentiation factors especially NIS, is a leading cause for BRAFV600E-related poor prognosis and mortality in thyroid tumorigenesis.
“Dedifferentiation and development of radioactive iodine (RAI) refractory diseases, resulted from decreased thyroid differentiation factors, especially sodium iodide symporter (NIS), is also the leading cause for BRAFV600E-related poor prognosis and mortality in thyroid tumorigenesis28–30.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [30]
Upregulation of pioneer developmental organizers such as SOX2, KLF4, β-catenin, SNAIL-1, c-MYC, TBX3, and BCL6 is reported downstream of BRAF/MAPK-driven tumor.
“Even upregulation of pioneer developmental organizers, such as SOX2, KLF4, β-catenin, SNAIL-1, c-MYC, TBX3, BCL6, et al., are reported downstream of BRAF/MAPK-driven tumor, the pathways causing lineage reprogramming are not clear12,15,30–36.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [30]
PTC patients with RET/PTC rearrangements or BRAFV600E mutation exhibit cell dedifferentiation.
“PTC patients with RET/PTC rearrangements [30–32] or the BRAFV600E mutation [33, 34] exhibit cell dedifferentiation.”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [34]
Cites
Mutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674 · see citing works
Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF
Wan, P., Garnett, M. J., Roe, S. M., Lee, S., Niculescu‐Duvaz, D., Good, V. M., Cancer Genome Project, Jones, C. M., Marshall, C. J., Springer, C. J., et al. (2004) · Cell · doi:10.1016/s0092-8674(04)00215-6 · Cited by 2,799 · see citing works
Kimura, E. T., Nikiforova, M. N., Zhu, Z., Knauf, J. A., Nikiforov, Y. E., & Fagin, J. A. (2003) · PubMed · Cited by 1,510 · see citing works
Self-citationProcessing of gene expression data generated by quantitative real-time RT-PCR.
Muller, P. Y., Janovjak, H., Miserez, A. R., & Dobbie, Z. (2002) · PubMed · Cited by 1,410 · see citing works
The RAF proteins take centre stage
Wellbrock, C., Karasarides, M., & Marais, R. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1498 · Cited by 1,223 · see citing works
Nikiforova, M. N., Kimura, E. T., Gandhi, M., Biddinger, P. W., Knauf, J. A., Basolo, F., Zhu, Z., Giannini, R., Salvatore, G., Fusco, A., et al. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030838 · Cited by 1,036 · see citing works
Self-citationBRAF Mutation in Papillary Thyroid Carcinoma
Cohen, Y., Xing, M., Mambo, E., Guo, Z., Wu, G., Trink, B., Beller, U., Westra, W. H., Ladenson, P. W., & Sidransky, D. (2003) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/95.8.625 · Cited by 917 · see citing works
Garnett, M. J., & Marais, R. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.022 · Cited by 794 · see citing works
The Raf/MEK/ERK pathway: new concepts of activation
Peyssonnaux, C., & Eychène, A. (2001) · Biology of the Cell · doi:10.1016/s0248-4900(01)01125-x · Cited by 734 · see citing works
BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC
Soares, P., Trovisco, V., Rocha, A. S., Lima, J. P., Castro, P., Preto, A., Máximo, V., Botelho, T. O., Seruca, R., & Sobrinho-Simões, M. A. (2003) · Oncogene · doi:10.1038/sj.onc.1206706 · Cited by 669 · see citing works
Kebebew, E., Greenspan, F. S., Clark, O. H., Woeber, K. A., & McMillan, A. (2005) · Cancer · doi:10.1002/cncr.20936 · Cited by 668 · see citing works
Nikiforov, Y. E., Rowland, J. M., Bove, K. E., Monforte-Muñoz, H., & Fagin, J. A. (1997) · PubMed · Cited by 666 · see citing works
Self-citationClinical Implication of Hot SpotBRAFMutation, V599E, in Papillary Thyroid Cancers
Namba, H., Nakashima, M., Hayashi, T., Hayashida, N., Maeda, S., Rogounovitch, T., Ohtsuru, A., Saenko, V., Kanematsu, T., & Yamashita, S. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030305 · Cited by 532 · see citing works
The ins and outs of Raf kinases
Daum, G., Eisenmann-Tappe, I., Fries, H.-W., Troppmair, J., & Rapp, U. R. (1994) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(94)90133-3 · Cited by 524 · see citing works
Kimura, T., Keymeulen, A. V., GOLSTEIN, J., Fusco, A., Dumont, J. E., & Roger, P. P. (2001) · Endocrine Reviews · doi:10.1210/edrv.22.5.0444 · Cited by 483 · see citing works
Anaplastic Thyroid Carcinoma: A Study of 70 Cases
Carcangiu, M. L., Steeper, T. A., Zampi, G., & Rosaí, J. (1985) · American Journal of Clinical Pathology · doi:10.1093/ajcp/83.2.135 · Cited by 466 · see citing works
Raf proteins and cancer: B-Raf is identified as a mutational target
Mercer, K., & Pritchard, C. A. (2003) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(03)00016-7 · Cited by 455 · see citing works
High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines.
Xu, X., Quiros, R. M., Gattuso, P., Ain, K. B., & Prinz, R. A. (2003) · PubMed · Cited by 415 · see citing works
Zhu, Z., Gandhi, M., Nikiforova, M. N., Fischer, A. H., & Nikiforov, Y. E. (2003) · American Journal of Clinical Pathology · doi:10.1309/nd8d-9laj-trct-g6qd · Cited by 371 · see citing works
Self-citationBRAF mutations are associated with some histological types of papillary thyroid carcinoma
Trovisco, V., de Castro, I. V., Soares, P., Máximo, V., Silva, P., Magalhães, J., AIu, A., Matías‐Guiu, X., & Sobrinho-Simões, M. A. (2004) · The Journal of Pathology · doi:10.1002/path.1511 · Cited by 361 · see citing works
Zhu, Z., Gandhi, M., Nikiforova, M. N., et al. (2003) · American Journal of Clinical Pathology · doi:10.1309/nd8d9lajtrctg6qd · Cited by 356 · see citing works
Levothyroxine Therapy in Patients with Thyroid Disease
Mandel, S. J., Brent, G. A., & Larsen, P. R. (1993) · Annals of Internal Medicine · doi:10.7326/0003-4819-119-6-199309150-00009 · Cited by 324 · see citing works
Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas
Jhiang, S. M., Sagartz, J. E., Tong, Q., Parker‐Thornburg, J., Capen, C. C., Cho, J. Y., Xing, S., & Ledent, C. A. (1996) · Endocrinology · doi:10.1210/endo.137.1.8536638 · Cited by 313 · see citing works
BRAF mutations in papillary carcinomas of the thyroid
Fukushima, T., Suzuki, S., Mashiko, M., Ohtake, T., Endo, Y., Takebayashi, Y., Sekikawa, K., Hagiwara, K., & Takenoshita, S. (2003) · Oncogene · doi:10.1038/sj.onc.1206739 · Cited by 294 · see citing works
Frattini, M., Ferrario, C., Bressan, P., Balestra, D., Cecco, L. D., Mondellini, P., Bongarzone, I., Collini, P., Gariboldi, M., Pilotti, S., et al. (2004) · Oncogene · doi:10.1038/sj.onc.1207980 · Cited by 264 · see citing works
The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.
Powell, D. J., Russell, J. P., Nibu, K., Li, G., Rhee, E. N., Liao, M., Goldstein, M., Keane, W. M., Santoro, M. M., Fusco, A., et al. (1998) · PubMed · Cited by 255 · see citing works
One- and Two-Step Transformations of Rat Thyroid Epithelial Cells by Retroviral Oncogenes
Fusco, A., Berlingieri, M. T., Fiore, P. P. D., et al. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.9.3365-3370.1987 · Cited by 246 · see citing works
Mutations of the BRAF Gene in Papillary Thyroid Carcinoma in a Korean Population
Kim, K., Kang, D., Kim, S. H., Seong, I. O., & Kang, D. Y. (2004) · Yonsei Medical Journal · doi:10.3349/ymj.2004.45.5.818 · Cited by 229 · see citing works
Long-Term Outcome of Patients With Differentiated Thyroid Carcinoma: Effect of Therapy
Mazzaferri, E. L. (2000) · Endocrine Practice · doi:10.4158/ep.6.6.469 · Cited by 201 · see citing works
Suzuki, H., Willingham, M. C., & Cheng, S.-Y. (2002) · Thyroid · doi:10.1089/105072502320908295 · Cited by 191 · see citing works
Knauf, J., Kuroda, H., Basu, S., & Fagin, J. (2003) · Oncogene · doi:10.1038/sj.onc.1206602 · Cited by 191 · see citing works
Self-citationBegum, S., Rosenbaum, E., Henrique, R., Cohen, Y., Sidransky, D., & Westra, W. H. (2004) · Modern Pathology · doi:10.1038/modpathol.3800198 · Cited by 175 · see citing works
Molecular Mechanisms of RET Activation in Human Cancer
Santoro, M., Melillo, R. M., Carlomagno, F., Fusco, A., & Vecchio, G. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04102.x · Cited by 172 · see citing works
Pohlenz, J., MAQUEEM, A., Cua, K., Weiss, R. E., SANDE, J. V., & Refetoff, S. (1999) · Thyroid · doi:10.1089/thy.1999.9.1265 · Cited by 154 · see citing works
Self-citationFagin, J. A. (2004) · Journal of Endocrinology · doi:10.1677/joe.1.05895 · Cited by 154 · see citing works
Self-citationp16 is a major inactivation target in hepatocellular carcinoma
Baek, M. J., Piao, Z., Kim, N., Park, C., Shin, E., Park, J. H., Jung, H., Kim, C. G., & Kim, H. (2000) · Cancer · doi:10.1002/1097-0142(20000701)89:1 · Cited by 116 · see citing works
Loss of p53 Promotes Anaplasia and Local Invasion in ret/PTC1-Induced Thyroid Carcinomas
Perle, K. M. D. L., Jhiang, S. M., & Capen, C. C. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64577-4 · Cited by 105 · see citing works
Multiple Ras Downstream Pathways Mediate Functional Repression of the Homeobox Gene Product TTF-1
Missero, C., Pirro, M. T., & Lauro, R. D. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.8.2783-2793.2000 · Cited by 63 · see citing works
Nguyen, L. Q., Kopp, P. A., Martinson, F. A., Stanfield, K., Roth, S. I., & Jameson, J. L. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.9.0516 · Cited by 62 · see citing works
Moeller, L. C., Kimura, S., Kusakabe, T., Liao, X.-H., SANDE, J. V., & Refetoff, S. (2003) · Molecular Endocrinology · doi:10.1210/me.2003-0175 · Cited by 61 · see citing works
Self-citationSerum Tests for Measurement of Thyroid Function
Robin, N. I., Hagen, S. R., Collaço, F. M., et al. (1971) · Hormone Research in Paediatrics · doi:10.1159/000178240 · Cited by 61 · see citing works
Early cellular abnormalities induced by RET/PTC1 oncogene in thyroid-targeted transgenic mice
Cho, J., Sagartz, J. E., Capen, C. C., et al. (1999) · Oncogene · doi:10.1038/sj.onc.1202709 · Cited by 60 · see citing works
Thyroid Carcinomas in RET/PTC Transgenic Mice
Jhiang, S. M., Cho, J.-Y., Furminger, T. L., et al. (1998) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-642-46870-4_17 · Cited by 55 · see citing works
Ras-mediated apoptosis of PC CL 3 rat thyroid cells induced by RET/PTC oncogenes
Castellone, M. D., Cirafici, A. M., Vita, G. D., Falco, V. D., Malorni, L., Tallini, G., Fagin, J. A., Fusco, A., Melillo, R. M., & Santoro, M. M. (2003) · Oncogene · doi:10.1038/sj.onc.1206112 · Cited by 49 · see citing works
Self-citationPowell, D. J., Russell, J. P., Li, G., Kuo, B. A., Fidanza, V., Huebner, K., & Rothstein, J. L. (2001) · Oncogene · doi:10.1038/sj.onc.1204425 · Cited by 46 · see citing works
Boelaert, K., Horacek, Y., Daykin, J., et al. (2004) · 23rd Joint Meeting of the British Endocrine Societies with the European Federation of Endocrine Societies · Cited by 1 · see citing works
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DeLellis, R. A. (2006) · Journal of Surgical Oncology · doi:10.1002/jso.20700 · Cited by 181 · see citing works
New therapeutic approaches for metastatic thyroid carcinoma
Baudin, E., & Schlumberger, M. (2007) · The Lancet Oncology · doi:10.1016/s1470-2045(07)70034-7 · Cited by 143 · see citing works
Chen, H., Luo, D., Zhang, L., Lin, X., Luo, Q., Yi, H., Wang, J., Yan, X., Li, B., Chen, Y., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17398 · Cited by 29 · see citing works
Self-citationZhang, Z., Wu, Y., Fu, J., Yu, X., Su, Y., Jia, S., Cheng, H., Shen, Y., He, X., Ren, K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48173-9 · Cited by 14 · see citing works
“Dedifferentiation and development of radioactive iodine (RAI) refractory diseases, resulted from decreased thyroid differentiation factors, especially sodium iodide symporter (NIS), is also theleadingcauseforBRAF V600E -relatedpoorprognosisandmortalityin thyroid tumorigenesis 28 – 30 .”
BackgroundRethinking the role of oncogenes in papillary thyroid cancer initiation
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- Authors
- Knauf, J. A., Ma, X., Smith, E. P., Zhang, L., Mitsutake, N., Liao, X.-H., Refetoff, S., Nikiforov, Y. E., & Fagin, J. A.
- Affiliations
- 1Division of Endocrinology and
- 3Medicine and
- University of Chicago (US)
- University of Cincinnati (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2005-05-15
- Volume
- 65
- Issue
- 10
- Pages
- 4238-4245
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2166568854
- Cited by
- 414
- References
- 46
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 13 · 2023: 18 · 2022: 20 · 2021: 17 · 2020: 7 · 2019: 15 · 2018: 11 · 2017: 13 · 2016: 20 · 2015: 19 · 2014: 28 · 2013: 35 · 2012: 19
- FWCI
- 17.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 50706, R01CA050706)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- BrafV600E, papillary thyroid carcinoma, transgenic mice, tall cell variant, poorly differentiated carcinoma, dedifferentiation, thyroid-stimulating hormone, thyroid dysfunction, goiter, tumor invasion, thyroid cancer pathogenesis
- MeSH terms
- Animals, Carcinoma, Papillary, Cell Differentiation, Female, Humans, Male, Mice, Transgenic, Mutation, Pregnancy, Thyroid Neoplasms, Blotting, Southern, Transgenes, MAP Kinase Signaling System, Proto-Oncogene Proteins B-raf, Mice
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