Mouse models of sporadic thyroid cancer derived from BRAF(V600E) alone or in combination with PTEN haploinsufficiency under physiologic TSH levels

The BRAF(V600E) mutation is the most prevalent driver mutation of sporadic papillary thyroid cancers (PTC). It was previously shown that prenatal or postnatal expression of BRAF(V600E) under elevated TSH levels induced thyroid cancers in several genetically engineered mouse models. In contrast, we found that postnatal expression of BRAF(V600E) under physiologic TSH levels failed to develop thyroid cancers in conditional transgenic Tg(LNL-Braf(V600E)) 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 Braf(CA/+) mice carrying a Cre-activated allele of Braf(V600E) exhibited higher transformation efficiency than Tg(LNL-Braf(V600E)) mice when crossed with TPO-Cre mice. As a result, most Braf(CA/+) 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 Braf(CA/+);Pten(f/+) 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 BRAF(V600E) alone under physiologic TSH levels induces PTC. Simultaneous PTEN haploinsufficiency tends to promote tumor growth and de-differentiation.