Meeting Program and Abstracts

BRAF V600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC) and is the main driver in the tumorigenesis of PTC through constitutive activation of MAPK signaling pathway.b-catenin (encoded by CTNNB1) is a key downstream component of canonical Wnt signaling pathway and is often overexpressed in PTC or mutated in anaplastic thyroid cancer.BRAF V600E -driven tumors have been speculated to rely on Wnt/bcatenin signaling to sustain its growth and progression, although the details of this interaction remain to be determined.The current study investigated the role of b-catenin in Braf V600E -driven thyroid cancer in a genetically engineered mouse model.Two genetically engineered mouse strains were used: LSL-Braf V600E and LSL-Ctnnb1 null .These two conditional Braf V600E knock-in and Ctnnb1 knockout mice were bred with TPO-Cre mice to produce thyroidspecific expression of Braf V600E Ctnnb1 null (BVE-Ctnnb1 null ) and Braf V600E Ctnnb1 wt (BVE-Ctnnb1 wt ) strains, respectively.Thyroid tumor progression and survival were evaluated in BVE-Ctnnb1 null and BVE-Ctnnb1 wt mice.Overexpression of Ctnnb1 was observed in thyroid tumors from BVE-Ctnnb1 wt mice.Following Ctnnb1 knockout, thyroid tumors became more localized with evidence of re-differentiation into follicular architecture.The overall survival of BVE-Ctnnb1 null mice was increased by more than 50% during 13month observation (p < 0.001, n = 20).Mechanistically, this phenotype was associated with down-regulation of MAPK, PI3K/Akt, and epithelial-mesenchymal transition, and increased expression of Ecadherin and genes for thyroid hormone synthesis such as Tg, Tpo, Tshr, and Slc5a5 (sodium-iodide symporter).Slc5a5 was the most impacted gene by Ctnnb1 knockout with 18-fold increase in RNA expression in thyroid tumors.PET/CT scan demonstrated significantly higher thyroid uptake of I 124 in BVE-Ctnnb1 null mice than BVE-Ctnnb1 wt mice.Our results indicate that Wnt/b-catenin pathway plays an important role in Braf V600E -mediated thyroid cancer progression.Inhibition of Ctnnb1 partially restores iodine uptake in thyroid cancer cells.Targeting Ctnnb1 may have significant benefit for radioactive iodine-refractory thyroid cancer.