Targeted Expression of BRAFV600E in Thyroid Cells of Transgenic Mice Results in Papillary Thyroid Cancers that Undergo Dedifferentiation

Abstract

The BRAF T1799A 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 BRAF T1799A are often invasive and present at a more advanced stage. BRAF T1799A 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 BRAF V600E in thyroid cancer pathogenesis, we targeted its expression to thyroid cells of transgenic FVB/N mice with a bovine thyroglobulin promoter. Two Tg-BRAF V600E 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 f2-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 tallcell 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 BRAF V600E 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. (Cancer Res 2005; 65(10): 4238-45)

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

“…In the study of Nikiforova et al (7), all BRAF-mutant poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and the BRAF V600E mutation was present in both the well-differentiated and dedifferentiated components, suggesting that it may have contributed to the transition from PTC to anaplastic carcinoma. In support of this hypothesis, thyroid-specific expression of BRAF V600E induces goiter and invasive PTC, which transitions to poorly differentiated carcinomas (14).…”

“…Mitsutake et al recently showed that BRaf is the key mediator of rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) -induced extracellular signal-regulated kinase (ERK) phosphorylation in thyroid cells (13). Thyroid-specific expression of BRAF V600E induces goiter and invasive papillary carcinoma, which transitions to poorly differentiated carcinoma (14). The precise effect of BRAF mutations in the clinical aggressiveness of thyroid carcinomas, as well as its potential role as a therapeutic target, is still under investigation.…”

An update on molecular biology of thyroid cancers

“…The results revealed that these transgenic animals had PTCs and showed invasion, a common property of aggressive tumors [35]. All these data suggest that mutations in BRAF can be used as a novel marker for the prognosis of thyroid cancer.…”

Surgical Perspective of T1799A BRAF Mutation Diagnostic Value in Papillary Thyroid Carcinoma

“…Other mutation involving in PTC is RAS mutation which occurs in 10-20% of tumors and this mutation in PTC almost always follicular variant in histology. Solid variant of PTC also has a different type of mutation which is associated with RET/PTC3 rearrangement (Knauf et al, 2005;Nikiforova and Nikiforov, 2009). Although BRAF mutation as a diagnostic test is specific for PTC, there are studies that stated its limitation as a diagnostic tool because of its low sensitivity (Xing, 2007;2009) There are some studies evaluated BRAF mutation diagnostic value.…”