BRAFV600E Overrides NOTCH Signaling in Thyroid Cancer.

Traversi, Florian; Stooss, Amandine; Dettmer, Matthias S.; Charles, Roch-Philippe (2021). BRAFV600E Overrides NOTCH Signaling in Thyroid Cancer. Thyroid, 31(5), pp. 787-799. Mary Ann Liebert 10.1089/thy.2019.0595

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Traversi, Florian; Stooss, Amandine; Dettmer, Matthias and Charles, Roch-Philippe

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1050-7256

Publisher:

Mary Ann Liebert

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

12 Jan 2021 07:55

Last Modified:

09 May 2021 01:32

Publisher DOI:

10.1089/thy.2019.0595

PubMed ID:

33012268

Uncontrolled Keywords:

ATC HES HEY PTC RBP genetically engineered mice

BORIS DOI:

10.48350/150867

URI:

https://boris.unibe.ch/id/eprint/150867

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