Abstract
The BRAFV600E mutation is the most prevalent driver mutation of sporadic papillary thyroid cancers (PTC). It was previously shown that prenatal or postnatal expression of BRAFV600E under elevated TSH levels induced thyroid cancers in several genetically engineered mouse models. In contrast, we found that postnatal expression of BRAFV600E under physiologic TSH levels failed to develop thyroid cancers in conditional transgenic Tg(LNL-BrafV600E) mice injected in the thyroid with adenovirus expressing Cre under control of the thyroglobulin promoter (Ad-TgP-Cre). In this study, we first demonstrated that BrafCA/+ mice carrying a Cre-activated allele of BrafV600E exhibited higher transformation efficiency than Tg(LNL-BrafV600E) mice when crossed with TPO-Cre mice. As a result, most BrafCA/+ mice injected with Ad-TgP-Cre developed thyroid cancers in 1 year. Histologic examination showed follicular or cribriform-like structures with positive TG and PAX staining and no colloid formation. Some tumors also had papillary structure component with lower TG expression. Concomitant PTEN haploinsufficiency in injected BrafCA/+;Ptenf/+ mice induced tumors predominantly exhibiting papillary structures and occasionally undifferentiated solid patterns with normal to low PAX expression and low to absent TG expression. Typical nuclear features of human PTC and extrathyroidal invasion were observed primarily in the latter mice. The percentages of pERK-, Ki67- and TUNEL-positive cells were all higher in the latter. In conclusion, we established novel thyroid cancer mouse models in which postnatal expression of BRAFV600E alone under physiologic TSH levels induces PTC. Simultaneous PTEN haploinsufficiency tends to promote tumor growth and de-differentiation.
Highlights
Sporadic thyroid cancers usually develop via abnormal activation of the RAS-RAF-MEK-ERK signaling pathway (MAPK; which relays signals from cell membrane to nucleus), primarily as a result of point mutations in the RAS/BRAF genes or chromosomal rearrangements such as RET/papillary thyroid cancers (PTC) translocations [1]
This model had various limitations, including (i) BRAFV600E was expressed in all thyroid cells from the fetal period, suggesting that this is a model of hereditary rather than sporadic thyroid cancers; (ii) serum TSH levels were elevated by BRAFV600E-mediated suppression of thyroid function, which by itself can induce thyroid goiters and sometimes tumors; and (iii) BRAFV600E expression was controlled by the Tg promotor rather than the original Braf promoter [3]
We show that postnatal BRAFV600E expression alone under physiologic TSH levels is sufficient for thyroid cancer development
Summary
Sporadic thyroid cancers usually develop via abnormal activation of the RAS-RAF-MEK-ERK signaling pathway (MAPK; which relays signals from cell membrane to nucleus), primarily as a result of point mutations in the RAS/BRAF genes or chromosomal rearrangements such as RET/PTC translocations [1]. The carcinogenicity of BRAFV600E in the thyroid glands was first demonstrated in vivo in Tg-BrafV600E transgenic mice expressing BRAFV600E under control of thyroid-specific thyroglobulin (Tg) promoter; these mice developed thyroid cancers very early in life [2] This model had various limitations, including (i) BRAFV600E was expressed in all thyroid cells from the fetal period, suggesting that this is a model of hereditary rather than sporadic thyroid cancers; (ii) serum TSH levels were elevated by BRAFV600E-mediated suppression of thyroid function, which by itself can induce thyroid goiters and sometimes tumors; and (iii) BRAFV600E expression was controlled by the Tg promotor rather than the original Braf promoter [3]. BrafCA;TPOCreER mice were reported to develop thyroid cancers after birth (after administration of tamoxifen), TSH increased slightly (
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
