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

Author:

Kim MinjunORCID,Kim Su-jinORCID,Ha Seong Yun,Xu Zhen,Han Youngjin,Jee Hyeon-Gun,Cho Sun Wook,Park Young Joo,Lee Kyu Eun

Abstract

Background: Cross-talk between mitogen-activated protein kinase and estrogen has been reported; however, the role of <i>BRAF<sup>V600E</sup></i> in the estrogen responsiveness of thyroid cancer is unknown. We elucidated the effect of <i>BRAF<sup>V600E</sup></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<sup>V600E</sup></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<sup>V600E</sup></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<sup>V600E</sup></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<sup>V600E</sup></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<sup>V600E</sup></i> mutation plays a crucial role in the estrogen responsiveness of thyroid cancer by regulating ER expression. Therefore, <i>BRAF<sup>V600E</sup></i> might be used as a biomarker when deciding future hormone therapies based on estrogen signaling in thyroid cancer patients.

Funder

National Research Foundation of Korea

Ministry of Science, ICT and Future Planning

Seoul National University Hospital

American Thyroid Association

Korean Cancer Association

Publisher

Korean Endocrine Society

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism

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