β-Catenin Attenuation Inhibits Tumor Growth and Promotes Differentiation in a BRAFV600E-Driven Thyroid Cancer Animal Model

Abstract

BRAF^V600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). β-Catenin (Ctnnb1) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAF ^V600E-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 Braf^V600E -driven thyroid cancer in a transgenic mouse model. In Braf ^V600E mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1^WT or BVE), overexpression of β-catenin was observed in thyroid tumors. In Braf ^V600E mice with Ctnnb1 knockout (BVE-Ctnnb1^null), 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 ¹²⁴iodine uptake, and serum T4. The survival of BVE-Ctnnb1^null 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^null tumors. Treatment with dual β-catenin/KDM4A inhibitor PKF118-310 dramatically improved the sensitivity of BVE-Ctnnb1^WT tumor cells to BRAF^V600E inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro, and tumor regression and differentiation in vivo These findings indicate that β-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAF^V600E inhibitors. Simultaneously targeting both Wnt/β-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAF^V600E inhibitor-resistant and/or radioiodine-refractory thyroid cancer.