Endocrine Abstracts

The thyroid hormone receptors (TRs) are ligand-dependent transcription factors regulating growth, development, and differentiation. That TRs are cellular homologs of the retroviral v-erbA oncogene suggests their possible involvement in carcinogenesis. Recent studies showed altered expression of TRs at both the mRNA and protein levels and identified somatic mutations of TRs in several human cancers, including thyroid carcinomas. We have created a knockin mutant mouse by targeting a mutation (PV) into the TRβ gene (TRβPV mouse). The PV mutation, identified in a patient with resistance to thyroid hormone, has lost T3 binding and transcriptional activity. TRβ^PV/PV mice spontaneously develop follicular thyroid carcinoma through pathological progression of hyperplasia, capsular and vascular invasion, anaplasia, and metastasis similar to human thyroid cancer. Consistent with human follicular thyroid carcinomas, phosphatidylinositol 3-kinase (PI3K) and AKT are activated during thyroid carcinogenesis of TRβ^PV/PV mice. Biochemical and molecular analysis uncovered that PV physically interacts with the regulatory p85α subunit, thereby activating the PI3K activity. Further analysis revealed that its downstream AKT-mammalian target of the rapamycin (mTOR)-p70^S6K signaling and the integrin-linked kinase-matrix metalloproteinase-2 (MMP-2) pathway are activated to promote tumor progression. TRβ^PV/PV mice were treated with LY294002 (LY), a potent PI3K inhibitor to evaluate its effects on the spontaneous development of thyroid cancer. LY treatmentinhibits the AKT-mTOR-p70^S6K signaling to inhibit tumor cell proliferation. LY treatment increases caspase 3 and decreases phosphorylated BAD to induce apoptosis. LY treatment reduces the AKT-MMP-2 signaling to decrease cell motility, thus blocking metastatic spread of thyroid tumors. These altered signaling pathways converge effectively to prolong survival of LY-treated TRβ^PV/PV mice. Thus, a mutated TRβ, PV, acts as a novel oncogene via protein–protein interaction to activate a tumor promoter, PI3K. The TRβ^PV/PV mouse, therefore, is a preclinical model showing that PI3K is a potential therapeutic target for thyroid cancer.