KRAS and thyroid hormone receptor β mutants induce undifferentiated thyroid cancer in mice via MYC upregulation

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NCI	CANCER-25

* FARE Award Winner

Author

• X Zhu

Abstract

Undifferentiated thyroid carcinoma is one of the most aggressive human cancers with frequent RAS mutations. How RAS gene contributes to cancer development remains largely unknown. Thyroid hormone receptor (TR) β (TRβ) mutants are identified in patients with thyroid hormone resistance and thyroid cancer. Mice harboring a TR mutant ThrbPV (ThrbPV/PV) spontaneously develop well-differentiated follicular thyroid cancer. We hypothesized that common RAS oncogenes and TRβPV together might initiate undifferentiated thyroid cancer. We targeted KrasG12D specifically in thyroid to generate double mutant mice (ThrbPV/PVKrasG12D mice) and to examine whether the double mutant mice developed undifferentiated thyroid cancer. Double mutant mice had poorer survival due to markedly aggressive thyroid tumors than ThrbPV/PV mice. Importantly, the mice developed frequent anaplastic foci with the complete loss of normal thyroid follicular morphology. Within anaplastic foci, thyroid specific transcription factor Paired box gene-8 (PAX8) expression was virtually lost. We found that elevated MYC protein had an inverse association with PAX8 and thyroid transcription factor-1 expression. In rat thyroid pccl3 cells, the expression of KRASG12D together with TRβPV upregulated MYC levels and MYC with TRβPV repressed the Pax8 upstream enhancer activity. Our findings indicated that MYC might serve as a potential target for therapeutic intervention.

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