BRAF(V600E) Mutation Enhances Estrogen-Induced Metastatic Potential of Thyroid Cancer by Regulating the Expression of Estrogen Receptors

BACKGROUND: Cross-talk between mitogen-activated protein kinase and estrogen has been reported; however, the role of BRAF(V600E) in the estrogen responsiveness of thyroid cancer is unknown. We elucidated the effect of BRAF(V600E) 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 BRAF gene (Nthy/WT) and Nthy/BRAF(V600E) (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. ESR expression was analyzed according to BRAF(V600E) 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. BRAF(V600E)-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 BRAF(V600E) group, ESR1/ESR2 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 BRAF(V600E) mutation plays a crucial role in the estrogen responsiveness of thyroid cancer by regulating ER expression. Therefore, BRAF(V600E) might be used as a biomarker when deciding future hormone therapies based on estrogen signaling in thyroid cancer patients.