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

Abstract

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 (CNC), 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 one 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 follicular thyroid cancer that exhibits a similar phenotype when modeled in the mouse. In addition to adding 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 follicular thyroid cancer.

Follicular Thyroid Cancers Demonstrate Dual Activation of PKA and mTOR as Modeled by Thyroid-Specific Deletion of Prkar1a and Pten in Mice

“…A number of genetic lesions have been identified in human FTC, including mutations in RAS, PTEN, and the PPARG-PAX8 fusion gene, but the connection between these mutations and carcinogenesis is less clear, especially because mouse models carrying these mutations singly either do not generate FTC (Ras and Pparg-Pax8) or generate it only unreliably (Pten deletion). In contrast, we recently demonstrated that thyroid-specific KO of Prkar1a leads to FTC in more than 40% of mice by 1 year of age (8). However, these tumors did not exhibit hematogenous metastasis, a key feature of human FTC.…”

“…In addition to data from R1a- (8) and DRP-TpoKO mice, we also generated microarray data from our own colony of Pten-TpoKO mice, which exhibit benign follicular thyroid hyperplasia (Supplemental Table 3). These three mouse data sets were used to perform principal component (PC) analysis to compress and then identify trends in the data.…”

“…PRKAR1A, the type 1A regulatory subunit of the cAMPdependent protein kinase (protein kinase A, or PKA), is the most ubiquitous of the PKA regulatory subunits, and inactivation of PRKAR1A leads to enhanced PKA activity (7). More recently we have shown that deletion of Prkar1a in the mouse thyroid leads to locally invasive FTC without distant metastases (8).…”

Expression of protein kinase A regulatory subunits in benign and malignant human thyroid tissues: A systematic review

“…In another study, the thyroid-specific knockout of the PRKAR1A gene in mice also resulted in hyperthyroidism, and papillary and follicular thyroid cancer (26).…”

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

“…STAT3 is typically activated through phosphorylation at tyrosine 705 by intrinsic tyrosine kinase activity of activated growth factor receptors or cytokine receptor-associated Janus kinase, but GasPCR/adenylyl cyclase/cAMP/PKA signaling can also activate STAT3. [124][125][126][127] For example, G-protein a-subunit-activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype associated with STAT3 activation. 126 The…”