<P><B>1) PTEN insufficiency accelerates tumor progression in a mouse model of thyroid cancer</B></P><P>Mutations and deletion of PTEN (phosphatase and tensin homolog deleted from chromosome) occur frequently in human cancers, including thyroid cancer. However, despite many correlative data, it is not known how the deregulation of the PTEN signalling cascade leads to thyroid cancer.</P><P>To understand how PTEN affects thyroid carcinogenesis, we adopted the loss-of-function approach by crossing TRbetaPV/PV mice with heterozygous PTEN+/-mice to generate TRbetaPV/PV mice deficient in one allele of the PTEN gene (TRbetaPV/PVPTEN+/- mice) and evaluated the effect of PTEN insufficiency on the spontaneous development of thyroid carcinogenesis. Mice lacking both alleles of the PTEN gene are embryonic lethal and could not be studied. Molecular studies showed that PTEN insufficiency markedly increased cell proliferation and survival to promote thyroid tumor growth in TRbetaPV/PV mice. Strikingly, follicular thyroid cancer as well as distant metastases to the lung occurred much earlier and at a higher frequency in TRbetaPV/PVPTEN+/- mice than in TRbetaPV/PV mice. Our findings indicated that PTEN deficiency results in constitutive activation of the PI3K/AKT pathway to play a critical role in thyroid cancer progression and aggressiveness. Thus, these findings suggested that PTEN could be tested as a molecular target for prevention and treatment of thyroid cancer.</P> <P><B>2). Thyroid hormone receptors are tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma</B></P> <P>Aberrant expression and mutations of thyroid hormone receptor genes (TRs) are closely associated with several types of human cancers. These observations raised the possibility that TRs could function as tumor suppressors. However, direct evidence to unambiguously demonstrate that TRs could act to suppress tumor progression was still lacking. We therefore took advantage of mice with deletion of all functional TRs (TRalpha1-/-TRbeta-/- mice;double KO mice) to address this question. As the double KO mice aged, they spontaneously developed follicular thyroid carcinoma with pathological progression from hyperplasia to capsular invasion, vascular invasion, anaplasia, and metastasis to the lung, similar to human thyroid cancer. Detailed molecular analysis revealed that known tumor promoters such as pituitary tumor transforming gene were activated and tumor suppressors such as peroxisome proliferator-activated receptor gamma and p53 were suppressed during carcinogenesis. In addition, consistent with the human cancer, AKT-mTOR-p70S6K signaling and vascular growth factor and its receptor were activated to facilitate tumor progression. This report presents <I>in vivo</I>evidence that functional loss of both TRalpha1 and TRbeta genes promotes tumor development and metastasis. Thus, for the first time, TRs were shown to function as tumor suppressors in a mouse model of metastatic follicular thyroid cancer. This finding opens a new area of study of TR actions and the biology of thyroid cancer.</P>
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