BRAFV600E Mutation Enhances Estrogen-Induced Metastatic Potential of Thyroid Cancer by Regulating the Expression of Estrogen Receptors

Abstract

Background: Cross-talk between mitogen-activated protein kinase and estrogen has been reported; however, the role of <i>BRAF^V600E</i> in the estrogen responsiveness of thyroid cancer is unknown. We elucidated the effect of <i>BRAF^V600E</i> on the estrogen-induced increase in metastatic potential in thyroid cancer.Methods: Using a pair of cell lines, human thyroid cell lines which harbor wild type <i>BRAF</i> gene (Nthy/WT) and Nthy/<i>BRAF^V600E</i> (Nthy/V600E), the expression of estrogen receptors (ERs) and estrogen-induced metastatic phenotypes were evaluated. Susceptibility to ERα- and ERβ-selective agents was evaluated to confirm differential ER expression. <i>ESR</i> expression was analyzed according to <i>BRAF^V600E</i> status and age (≤50 years vs. >50 years) using The Cancer Genome Atlas (TCGA) data.Results: Estradiol increased the ERα/ERβ expression ratio in Nthy/V600E, whereas the decreased ERα/ERβ expression ratio was found in Nthy/WT. <i>BRAF^V600E</i>-mutated cell lines showed a higher E2-induced increase in metastatic potential, including migration, invasion, and anchorage-independent growth compared with Nthy/WT. An ERα antagonist significantly inhibited migration in Nthy/V600E cells, whereas an ERβ agonist was more effective in Nthy/WT. In the <i>BRAF^V600E</i> group, <i>ESR1/ESR2</i> ratio was significantly higher in younger age group (≤50 years) compared with older age group (>50 years) by TCGA data analysis.Conclusion: Our data show that <i>BRAF^V600E</i> mutation plays a crucial role in the estrogen responsiveness of thyroid cancer by regulating ER expression. Therefore, <i>BRAF^V600E</i> might be used as a biomarker when deciding future hormone therapies based on estrogen signaling in thyroid cancer patients.