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Published Online: 3 May 2021

BRAFV600E Overrides NOTCH Signaling in Thyroid Cancer

Publication: Thyroid
Volume 31, Issue Number 5


Background: Several mechanisms likely cooperate with the mitogen-activated protein (MAP)-kinase pathway to promote cancer progression in the thyroid. One putative pathway is NOTCH signaling, which is implicated in several other malignancies. In thyroid cancer, data regarding the role of the NOTCH pathway are insufficient and even contradictory.
Methods: A BRAFV600E-driven papillary thyroid carcinoma (PTC) mouse model was subjected to NOTCH pathway genetic alterations, and the tumor burden was followed by ultrasound. Further analyses were performed on PTC cell lines or noncancerous cells transfected with NOTCHIC or BRAFV600E, which were then subjected to pharmacological treatment with MAP-kinase or NOTCH pathway inhibitors.
Results: The presence of the BRAFV600E mutation coupled with overexpression of the NOTCH intracellular domain led to significantly bigger thyroid tumors in mice, to a more aggressive carcinoma, and decreased overall survival. Although more cystic, the tumors did not progress into anaplastic thyroid carcinomas. On the contrary, the deletion of RBP-jκ (a major cofactor involved in NOTCH signaling) did not alter the phenotype in mice. BRAFV600E-mutated PTC cell lines were resistant to pharmacological inhibition of the NOTCH pathway. Inhibition of MEK1/2 uncovered a predominant effect on Hes1/Hey1 transcription compared with NOTCH inhibition in BRAFV600E-mutated cell lines. Finally, γ-secretase activity and γ-secretase subunit transcription levels were dependent on ERK activation. Our findings suggest that MAP-kinase activity overrides the NOTCH pathway in the context of thyroid cancer.
Conclusions: The interaction between the BRAF and NOTCH pathways demonstrates that the BRAFV600E mutation might bypass NOTCH and exert a strong positive effect on NOTCH downstream targets in thyroid carcinoma.

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Published In

cover image Thyroid®
Volume 31Issue Number 5May 2021
Pages: 787 - 799
PubMed: 33012268


Published online: 3 May 2021
Published in print: May 2021
Published ahead of print: 12 November 2020
Published ahead of production: 3 October 2020


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Florian Traversi
Institute of Biochemistry and Molecular Medicine, and Swiss National Center of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.
Amandine Stooss
Institute of Biochemistry and Molecular Medicine, and Swiss National Center of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.
Matthias S. Dettmer
Institute of Pathology, University of Bern, Bern, Switzerland.
Roch-Philippe Charles [email protected]
Institute of Biochemistry and Molecular Medicine, and Swiss National Center of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.


Address correspondence to: Roch-Philippe Charles, PhD, Institute of Biochemistry and Molecular Medicine, Swiss National Center of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, Bern CH-3012, Switzerland [email protected]

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the Swiss National Foundation grant 31003A_149824/1. The laboratory of RPC is also supported by the Swiss National Science Foundation grant NCCR-TransCure.

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