Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice.

CONTEXT: Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC. OBJECTIVE: The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC. DESIGN: We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors. SETTING: The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals. PATIENTS: Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, five follicular variant PTC cases, and 10 FTC cases. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Mouse and patient samples were analyzed for expression of activated cAMP response element binding protein, AKT, ERK, and mammalian target of rapamycin (mTOR). Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression. RESULTS: Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of protein kinase A and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement. CONCLUSIONS: These data imply that the protein kinase A and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics.

The protein kinase A regulatory subunit R1A (Prkar1a) plays critical roles in peripheral nerve development.

Signaling through cAMP has been implicated in Schwann cell (SC) proliferation and myelination, but the signaling pathway components downstream of cAMP required for SC function remain unknown. Protein kinase A (PKA) is a potential downstream effector of cAMP. Here, we induced loss of Prkar1a, the gene encoding the type 1A regulatory subunit of PKA, in SC to study its role in nerve development; loss of Prkar1a is predicted to elevate PKA activity. Conditional Prkar1a knock-out in mouse SC (Prkar1a-SCKO) resulted in a dramatic and persistent axonal sorting defect, and unexpectedly decreased SC proliferation in Prkar1a-SCKO nerves in vivo. Effects were cell autonomous as they were recapitulated in vitro in Prkar1a-SCKO SC, which showed elevated PKA activity. In the few SCs sorted into 1:1 relationships with axons in vivo, SC myelination was premature in Prkar1a-SCKO nerves, correlating with global increase in the cAMP-regulated transcription factor Oct-6 and expression of myelin basic protein. These data reveal a previously unknown role of PKA in axon sorting, an unexpected inhibitory role of PKA on SC cell proliferation in vivo and define the importance of Prkar1a in peripheral nerve development.

Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer.

Thyroid cancer is the most common endocrine malignancy in the population, and the incidence of this cancer is increasing at a rapid rate. Although genetic analysis of papillary thyroid cancer (PTC) has identified mutations in a large percentage of patients, the genetic basis of follicular thyroid cancer (FTC) is less certain. Thyroid cancer, including both PTC and FTC, has been observed in patients with the inherited tumor predisposition Carney complex, caused by mutations in PRKAR1A. In order to investigate the role of loss of PRKAR1A in thyroid cancer, we generated a tissue-specific knockout of Prkar1a in the thyroid. We report that the resulting mice are hyperthyroid and developed follicular thyroid neoplasms by 1 year of age, including FTC in over 40% of animals. These thyroid tumors showed a signature of pathway activation different from that observed in other models of thyroid cancer. In vitro cultures of the tumor cells indicated that Prkar1a-null thyrocytes exhibited growth factor independence and suggested possible new therapeutic targets. Overall, this work represents the first report of a genetic mutation known to cause human FTC that exhibits a similar phenotype when modeled in the mouse. In addition to our knowledge of the mechanisms of human follicular thyroid tumorigenesis, this model is highly reproducible and may provide a viable mechanism for the further clinical development of therapies aimed at FTC.