β-Catenin Attenuation Inhibits Tumor Growth and Promotes Differentiation in a BRAF-Driven Thyroid Cancer Animal Model.

mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). β-Catenin () is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. -driven tumors have been speculated to rely on Wnt/β-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of β-catenin in -driven thyroid cancer in a transgenic mouse model. In mice with wild-type (WT) (BVE-Ctnnb1 or BVE), overexpression of β-catenin was observed in thyroid tumors. In mice with knockout (BVE-Ctnnb1), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated iodine uptake, and serum T4. The survival of BVE-Ctnnb1 mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGFβ pathways and loss of epithelial-mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1 tumors. Treatment with dual β-catenin/KDM4A inhibitor PKF118-310 dramatically improved the sensitivity of BVE-Ctnnb1 tumor cells to BRAF inhibitor PLX4720, resulting in significant growth arrest and apoptosis , and tumor regression and differentiation These findings indicate that β-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAF inhibitors. Simultaneously targeting both Wnt/β-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAF inhibitor-resistant and/or radioiodine-refractory thyroid cancer.