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Role of β-Catenin in BRAF -Mutant Papillary Thyroid Cancer

By: Lauren Harrison, MS
Posted: Wednesday, March 18, 2020

Papillary thyroid cancer with BRAF V600E mutations utilize the wnt/β-catenin pathway as they progress. Inhibition of the gene CTNNB1, which encodes β-catenin, may help to restore iodine uptake in thyroid cancer cells and possibly represent a therapeutic target. Yufei Shi, MD, of the King Fasial Specialist Hospital and Research Centre in Saudi Arabia, and colleagues presented this preclinical research at the 2019 American Thyroid Association Annual Meeting in Chicago (Abstract Oral 1) and published it in the journal Thyroid.

This study investigated the role of β-catenin in BRAF V600E–mutant thyroid cancer in a genetically engineered mouse model. Mice were bred to create progeny that had specific expression of BRAF V600E with CTNNB1-null or BRAF V600E and CTNNB1 wild-type mice. The thyroid tumor progression and survival were then evaluated in each strain of mice.

The overexpression of CTNNB1 was seen in thyroid tumors in mice that had wild-type CTNNB1. After CTNNB1 was knocked out, the thyroid tumors became much more localized and showed evidence of redifferentiation into follicular architecture. In addition, the overall survival of the CTNNB1 knockout mice was increased by more than 50% in the 13-month observation period.

The CTNNB1-null phenotype was associated with the downregulation of MAPK, PI3K/AKT, and the epithelial-mesenchymal transition with increased expression of E-cadherin. There was also an increase in genes required for thyroid hormone synthesis, such as thyroglobulin, thyroid peroxidase, thyroid-stimulating hormone receptor, and the sodium-iodine symporter. The sodium-iodine symporter seemed to be impacted most by CTNNB1 knockout, as it showed an 18-fold increase in RNA expression in these tumors. Of note, PET/CT scans showed increased uptake of radioactive iodine in the CTNNB1-null mice compared with the CTNNB1 wild-type mice.

Disclosure: Full disclosures of the study authors can be found at thyroid.org.

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