BRAF Overrides NOTCH Signaling in Thyroid Cancer.

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. A BRAF-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 NOTCH or BRAF, which were then subjected to pharmacological treatment with MAP-kinase or NOTCH pathway inhibitors. The presence of the BRAF 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. BRAF-mutated PTC cell lines were resistant to pharmacological inhibition of the NOTCH pathway. Inhibition of MEK1/2 uncovered a predominant effect on / transcription compared with NOTCH inhibition in BRAF-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. The interaction between the BRAF and NOTCH pathways demonstrates that the BRAF mutation might bypass NOTCH and exert a strong positive effect on NOTCH downstream targets in thyroid carcinoma.