"DESCRIPTION (provided by applicant): Thyroid cancer is the most common cancer of the endocrine glands, and it is also the cancer with the highest increase in incidence over the past 20 years. Differentiated epithelial thyroid cancers are divided into two subtypes based on their histopathological appearance. Papillary thyroid cancer (PTC) accounts for about 80% of cases, whereas follicular thyroid cancer (FTC) accounts for the majority of the remainder. Although FTC is less common, it is associated with a poorer prognosis because of its aggressive behavior and early metastasis. There are two autosomal dominant tumor syndromes in which patients are at increased risk for this thyroid pathology: Carney Complex (CNC) and Cowden syndrome (CS). At the genetic level, CNC is caused by mutations in the PRKAR1A tumor suppressor whereas CS is caused by mutations in the PTEN tumor suppressor. These mutations lead to hyperactivity of the PKA and PI3K-AKT signaling pathways, respectively. In the thyroid, PKA is known to signal downstream from thyroid stimulating hormone (TSH), and epidemiologic evidence connects increased TSH to increased risk for thyroid cancer. My laboratory has been studying tumorigenesis associated with mutations of PRKAR1A/Prkar1a, and we have recently generated Prkar1a thyroid specific KO mice that develop FTC within 1 year in >40% of animals. Further, we have developed evidence that mice with activation of both PKA (via Prkar1a KO) and Akt (via Pten KO) have aggressive and metastatic FTC which has significant similarities to the human disease. Based on our preliminary characterization of these models, we hypothesize that PKA signaling plays a central role in the development of follicular thyroid cancer. The behavior of these tumors depends on the interaction of PKA with other signaling cascades in the cell to either restrain or promote carcinogenesis and/or metastasis. To test this hypothesis, we propose three inter-related avenues of investigation. First, although our preliminary data demonstrates that PKA activation in the thyroid is carcinogenic, multiple prior studies have shown that TSH stimulation (which activates PKA and other pathways) is not. In Aim 1, we will identify the non-PKA pathways activated by TSH that suppress PKA's ability to produce thyroid cancers. Second, the experiments in Aim 2 will elucidate the molecular basis by which inactivation of Prkar1a combines with loss of Pten to produce an aggressive metastatic FTC phenotype. This Aim will include examination of a cohort of human FTC to determine if similar signaling alterations are observed. In Aim 3, we will build on preliminary data from both mouse and human FTCs indicating that mTOR activation occurs during carcinogenesis. We will characterize FTC-specific isoforms of the mTOR protein and its partners and probe the mechanism of mTOR activation. These data will be used to drive molecular analysis of these same processes in a large cohort of human tumors. Overall, the proposed studies should provide new insights into the biology of follicular thyroid cancers and help pave the way for the development of new modes of clinical treatment of this disease." |