BRAFV600E 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 BRAFV600E in the estrogen responsiveness of thyroid cancer is unknown. We elucidated the effect of BRAFV600E 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/BRAFV600E (Nthy/V600E), the expression of estrogen receptors (ERs) and estrogen-induced metastatic phenotypes were evaluated. Susceptibili-ty to ER alpha-and ERf3-selective agents was evaluated to confirm differential ER expression. ESR expression was analyzed according to BRAFV600E status and age (<= 50 years vs. >50 years) using The Cancer Genome Atlas (TCGA) data. Results: Estradiol increased the ER alpha/ERf3 expression ratio in Nthy/V600E, whereas the decreased ER alpha/ERf3 expression ratio was found in Nthy/WT. BRAFV600E-mutated cell lines showed a higher E2-induced increase in metastatic potential, including migration, invasion, and anchorage-independent growth compared with Nthy/WT. An ER alpha antagonist significantly inhibited migration in Nthy/ V600E cells, whereas an ERf3 agonist was more effective in Nthy/WT. In the BRAFV600E 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 BRAFV600E mutation plays a crucial role in the estrogen responsiveness of thyroid cancer by regulat-ing ER expression. Therefore, BRAFV600E might be used as a biomarker when deciding future hormone therapies based on estrogen signaling in thyroid cancer patients.

Automated summary

The BRAFV600E mutation plays a crucial role in the estrogen responsiveness of thyroid cancer by regulating the expression of estrogen receptors. This finding suggests that BRAFV600E could be used as a biomarker for hormone therapy decisions in thyroid cancer patients based on estrogen signaling.