Gene Dosage Affects Thyroid Cancer Histology and Differentiation In Vivo.

The transcription factor Forkhead box E1 () is a key player in thyroid development and function and has been identified by genome-wide association studies as a susceptibility gene for papillary thyroid cancer. Several cancer-associated polymorphisms fall into gene regulatory regions and are likely to affect expression levels. However, the possibility that changes in expression modulate thyroid cancer development has not been investigated. Here, we describe the effects of gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for null allele () were crossed with a -inducible cancer model to develop thyroid cancer in either a or genetic background. In mice, cancer histological features are quite similar to that of human high-grade papillary thyroid carcinomas, while cancers developed with reduced gene dosage maintain morphological features resembling less malignant thyroid cancers, showing reduced proliferation index and increased apoptosis as well. Such cancers, however, appear severely undifferentiated, indicating that levels affect thyroid differentiation during neoplastic transformation. These results show that dosage exerts pleiotropic effects on thyroid cancer phenotype by affecting histology and regulating key markers of tumor differentiation and progression, thus suggesting the possibility that could behave as lineage-specific oncogene in follicular cell-derived thyroid cancer.