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<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.

Association of DNA Promoter Methylation and BRAF Mutation in Thyroid Cancer

“…The B-Raf proto-oncogene ( BRAF ) encodes a cytoplasmic serine/threonine kinase with a key role in regulating the mitogen-activated protein kinase signal transduction pathway [ 9 ]. The BRAF V600E mutation in exon 15 of the BRAF gene has been studied in different cancers, including thyroid cancers [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Induction of the BRAF V600E mutation in thyroid cells may lead to frequent hypermethylation [ 21 ].…”

Editorial: Recent advances in papillary thyroid carcinoma: Progression, treatment and survival predictors

“…These were the tumor size, extrathyroid invasion, the T N M classification, and multifocality, which, with an intermediate value in terms of odds ratios, demonstrate the relevance of a higher BMI and the possible relation already reported with the female gender, where thyroid carcinoma has greater incidence. Additionally, the potential mitogenic effect of estrogens in thyroid cancer, which has been already reported (1), is considered, and its increased frequency in patients with breast cancer was explained in the presence of a hyperestrogenic state.…”

Thyroid Cancer Prevalence, Risk Exposure, and Clinical Features Among Transgender Female Veterans

“…The molecular mechanisms for a potential estrogen-induced increase in thyroid cancer incidence are incompletely understood [ 20 ]. Estrogens promote the growth of thyroid cells, but studies focused on the expression of estrogen receptor α and β in thyroid cancer specimens have been contradictory [ 14 , 21 ]. A role for G protein-coupled estrogen receptor has been proposed [ 22 ]; exogenous estradiol may also increase the expression of telomerase reverse transcriptase [ 23 ], expression of which is associated with progression and more aggressive features of thyroid cancer [ 24 , 25 ].…”