Pituitary tumorigenesis in Prkar1a +/- Aip +/- mice

Pituitary adenomas are a common condition causing significant morbidity, including impaired quality of life, and mortality due to excessive hormone secretion or mass effects. The rational development of medical therapies for pituitary adenomas is critically dependent on the understanding of the molecular mechanisms of pituitary tumorigenesis. Pituitary hormone secretion is regulated, amongst others, via the cAMP/PKA pathway. PRKAR1A loss of function mutations causing overactive PKA signaling are the molecular basis of Carney complex, a condition leading to multiple endocrine tumors including adrenocortical hyperplasia and pituitary adenomas (Kirschner et al, 2000a; Stratakis et al, 2001). PRKAR1A protein was shown to be reduced or absent in pituitary adenomas (Lania et al, 2004). Pituitary-specific Prkar1a -/- mice exhibited an increased prevalence of pituitary adenomas (Yin et al, 2008). However, the formation of autonomous pituitary adenomas is hypothesized to require an additional currently unknown genetic hit (Lania & Spada, 2009). Germline mutations of AIP are the genetic basis for familial isolated pituitary adenomas (FIPA), and Aip +/- mice have a pronounced propensity for the development of pituitary adenomas (Raitila et al, 2010; Vierimaa et al, 2006). AIP regulates the AHR-ARNT pathway, which controls transcription of xenobiotic metabolizing enzymes. AIP also interacts with members of the cAMP/PKA pathway including G13 and the phosphodiesterases PDE4A5 and PDE2A. However, the mechanisms governing pituitary tumorigenesis due to AIP loss of function are currently not known (Beckers et al, 2013; Trivellin & Korbonits, 2011). AIP status in pituitary adenomas predicts the response to medical therapy with somatostatin analogs and AIP function is therefore of particular interest with regard to therapeutic approaches (Gadelha et al, 2012). We hypothesize that a combination of AIP loss of function and PRKAR1A inactivation will induce pituitary tumorigenesis. Prkar1a and Aip heterozygous double-knockout mice will be investigated focusing on the formation of pituitary adenomas and other tumors. Studies in primary pituitary cultures as well as pituitary cell lines will provide further functional information on mechanisms of tumor formation and hormone secretion. Moreover, results could provide more detailed information on the mechanisms by which AIP contributes to pituitary tumorigenesis. In summary, the combined effects of increased PKA signaling in PRKAR1A loss of function, and the heterogeneous effects of AIP loss of function, could lead to pituitary adenoma formation, thereby elucidating the molecular basis of pituitary tumorigenesis and laying a foundation for the future development of novel medical treatments.