Abstract
Abstract Background: Carney Complex (CNC) is a multiple neoplasia syndrome inherited in an autosomal dominant manner and causing various endocrine and bone tumors. The PRKAR1A gene coding for the regulatory subunit type 1A of protein kinase A (PKA) is mutated in CNC patients, but tumorogenesis mechanisms are not well understood. Regulatory subunits suppress activity of catalytic subunits of PKA responsible for cAMP signaling and cell differentiation and maturation. Mice with a deleted prkar1a allele develop a variety of tumors overlapping those of CNC patients. Deletion of a catalytic subunit allele prkaca+/− on the prkar1a+/ background unexpectedly increased the numer and aggressiveness of bone tumors without development of schwannomas or thyroid lesions. Cells from prkar1a+/−prkaca+/ tumors have more type II PKA complexes, indicating that unbalanced expression of type II and type I regulatory subunits may also dysregulates PKA catalytic activity, potentially increasing tumorigenesis. Methods: To explore this hypothesis, single mice with single alleles of prkar1a, prkar2a and prkar2b were crossed to generate heterozygous mice for double heterozygotes prkar1a+/−/prkar2a+/− or prkar1a+/−/prkar2b+/− and double knockouts. The resulting mice of 3,6,9,12,18 month age were phenotyped and compared to prkar1a+/−. Tumor specimens were examined by histology, polarized microscopy and confocal Raman micro-spectroscopy. Results: Mice with both alleles prkar1a+/+ did not develop any tumors. Double heterozygotes developed bone tumors whose onset age was delayed to 9 months in prkar1a+/−/prkar2b+/− mice compared to 3-6 months in the others. However, the mean number of tumors per animal became similar for prkar1a+/− and double heterozygotes by 12 months. Histology of the bone tumors showed abnormal proliferation of a fibroblastoid-like cell with better osteogenic differentiation in the lesions from double heterozygous mice. Polarized microscopy and Raman micro-spectroscopy revealed that bone material growing in tumors was immature and poorly organized in prkar1a+/− mice (disorganized collagen and osteocytes and undermineralized matrix). Prkar2α+/− deletion on the prkar1α+/− background rescued local organization and mineralization but worsened global organization of cortical tumor bone. The prkar1a+/−/prkar2b+/− deletion rescued both global and local organization and mineralization, resulting in formation of mature bone. Conclusion: Prkar1a haploinsufficiency requires both prkar2a and prkar2b for tumorigenesis in most tissues except bone. In bone, however, prkar1a is the major tumor-suppressor gene. Unexpectedly, Prkar2b or prkar2a deficiencies in addition to prkar1a lead to better differentiation of bone tumors, indicating a compensating role for the type II regulatory subunits in bone tumirogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1360. doi:1538-7445.AM2012-1360
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