Endocrine Abstracts

Introduction: Worldwide constantly rising incidence of thyroid cancer promotes research activities. Nowadays the most speculated issue is the clinical significance of BRAF mutation. For sure BRAF mutation is a cancer-specific somatic mutation consistent with papillary thyroid cancer phenotype, otherwise, its role in tumor aggressiveness, progression, and the overall poor outcome is controversial. As far as several clinical studies claim opposing opinions, the learning aspect of mouse models comes to its point.

Objective: To evaluate the effect of BRAF V600E mutation on follicular cells of the thyroid gland in a mouse model, which imitates sporadic oncogenic pathway.

Methods: A transgenic mouse model of a spontaneous Cre activation in the absence of tamoxifen leading to focal instead of global BRAF V600E activation, under the Thyroglobulin promoter, was observed at several time points. Thyroid glands of these mice underwent different immunohistochemical stainings (IHCS), that were compared with wild-type controls.

Results: BRAF V600E mutation was gradually activated in follicular cells and some areas of the thyroid gland revealed after 6 months papillary formations with typical nuclear characteristics for carcinoma. From the very beginning, the follicles and so the whole thyroid gland was growing in size, without causing breathing impairment. Blood measurements were performed, confirming normal serum levels of T₄ and TSH. The oldest sacrificed mouse, aged 18 months, shown in each of its thyroid lobes several foci of papillary thyroid carcinoma (PTC). There were mainly areas of classical PTC, then solid PTC as well as the hobnail variant pattern. The proliferative rate (including Ki67 IHCS) was overall very low. Loss of thyroglobulin expression occurred early after mutant BRAF activation i.e. before overt tumor formation. In larger tumor formations further loss of dedifferentiation was documented by the loss of E-cadherin and weaker expression of Nkx2-1 (TTF-1) in 12 months or older mice. The tumor niche did not show any rapid involvement of inflammatory cells.

Conclusion: This mouse model imitates a sporadic oncogenic tumor initiation under the activation of BRAF V600E point mutation solely expressed in follicular cells of mice thyroid gland. The model recapitulates BRAF V600E-mediated tumor initiation, development, and progression that may be used for further investigation such as drug treatment with tyrosine kinase inhibitors or solely BRAF kinase inhibitors in different phases of papillary cancer growth.