Significant new advances in 2007-2008 are highlighted below. Phosphatidylinositol 3-kinase is a potential molecular target for the treatment of thyroid cancer Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B signaling pathway has been associated with multiple human cancers, including thyroid cancer. Recently we showed that, similar to human thyroid cancer, the PI3K-AKT pathway is overactivated in both the thyroid and metastatic lesions of a mouse model of follicular thyroid carcinoma (TRbetaPV/PV mice). This TRbetaPV/PV mouse harbors a knockin mutant thyroid hormone receptor beta gene (TRbetaPV mutant) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. That the activation of the PI3K-AKT signaling contributes to thyroid carcinogenesis raised the possibility that this pathway could be a potential therapeutic target in follicular thyroid carcinoma. We therefore tested this possibility by treating TRbetaPV/PV mice with LY294002 (LY), a potent and specific PI3K inhibitor, and evaluating the effect of LY on the spontaneous development of thyroid cancer. LY treatment inhibited the AKT-mammalian target of rapamycin (mTOR)-p70S6K signaling, and it decreased cyclin D1 and increased p27Kip1 expression to inhibit thyroid tumor growth and reduce tumor cell proliferation. LY treatment increased caspase 3 and decreased phosphorylated BAD to induce apoptosis. In addition, LY treatment reduced the AKT-matrix metalloproteinase 2 signaling to decrease cell motility to block metastatic spread of thyroid tumors. Thus, these altered signaling pathways converged effectively to prolong survival of TRbetaPV/PV mice treated with LY. No significant adverse effects were observed for wild type mice treated similarly with LY. Our study provides the first preclinical evidence for the in vivo efficacy for LY in the treatment of follicular thyroid cancer. Thus, PI3K is a potential molecular target to treat thyroid cancer. Phosphatidylinositol 3-kinase is a potential molecular target for the treatment of pituitary tumors Thyroid-stimulating hormone (TSH)-secreting pituitary tumors (TSHomas) are pituitary tumors that constitutively secrete TSH. Molecular mechanisms underlying this abnormality are largely undefined. As TRbetaPV/PV mice age, they spontaneously develop TSHomas. Using this mouse model, we investigated the role of the PI3K-AKT signaling pathway in the pathogenesis of TSHomas. Concurrent with aberrant growth of pituitaries, AKT and its downstream effectors mammalian target rapamycin (mTOR) and p70S6Kwere activated to contribute to increased cell proliferation and pituitary growth. In addition, activation of AKT led to decreased apoptosis by inhibiting pro-apoptotic activity of BAD, further contributing to the aberrant cell proliferation. These results suggest an activated PI3K-AKT pathway could underscore tumorigenesis, raising the possibility that this pathway could be a potential therapeutic target in TSHomas. Indeed, TRbetaPV/PV mice treated with a PI3K specific inhibitor, LY294002 (LY), showed a significant decrease in pituitary growth. The pro-growth signaling via AKT-mTOR-p70S6K and cyclin D1/cyclin-dependent kinase (CDK4) were inhibited and pro-apoptotic activity of BAD was increased by LY treatment. Thus, activation of the PI3K-AKT pathway mediates, at least in part, the aberrant pituitary growth, and the intervention of this signaling pathway presents a novel therapeutic opportunity for TSHomas. Regulation of beta-catenin by a novel nongenomic action of thyroid hormone beta receptor Analysis of altered gene expression patterns during thyroid carcinogenesis of TRbetaPV/PV mice showed that beta-catenin, which plays a critical role in oncogenesis, was highly elevated in thyroid tumors. We sought to understand the molecular basis underlying aberrant accumulation of beta-catenin by mutations of TRbeta in vivo . Cell-based studies showed that T3 induced the degradation of beta-catenin in cells expressing TRbeta via proteasomal pathways. In contrast, no T3-induced degradation occurred in cells expressing PV. In vitro binding studies and cell-based analyses revealed that beta-catenin physically associated with the unliganded TRbeta or PV. However, in the presence of T3, beta-catenin was dissociated from TRbeta/beta-catenin complexes, but not from PV/beta-catenin complexes. Beta-catenin signaling was repressed by T3 in TRbeta-expressing cells through decreasing beta-catenin-mediated transcription activity and target gene expression, whereas sustained beta-catenin signaling was observed in PV-expressing cells. The stabilization of beta-catenin, via association with a mutated TRbeta, represents a novel activating mechanism of the oncogenic beta-catenin that could contribute to thyroid carcinogenesis in TRbetaPV/PV mice.