Data from β-Catenin Attenuation Inhibits Tumor Growth and Promotes Differentiation in a BRAF<sup>V600E</sup>-Driven Thyroid Cancer Animal Model

Abstract

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