Session: SUN 303-321-Cancer in Endocrine Tissues
Bench to Bedside
Poster Board SUN-320
The wingless (Wnt) pathway influences embryonic development, including cell orientation, fate and self-renewal of stem cells. β-catenin is constitutively synthesized and degraded by a cytosolic destruction complex. Upon Wnt pathway activation, phosphorylation at S45, S33, S37 and T41 prevents degradation and allows β-catenin to enter the nucleus and mediate transcription of Wnt pathway target genes. Mutations at these loci in exon 3 of the b-catenin gene, CTNNB, prevent destruction in the absence of Wnt pathway activation. Such mutations are implicated in the tumorigenesis of ACPs (3-5) but have not been reported in PCPs. β-catenin also participates in the adherens junction complex, with E-cadherin, a-catenin, plakoglobin and p120. The role of the adherens junction has not been defined in CPs. We characterized a large cohort (98 CPs, 84 ACPs, 14 PCPs), for subcellular location of adherens junction components and key b-catenin mutations.
Nuclear β-catenin was found in discrete clusters or isolated epithelial cells in all of ACPs, but no PCPs, suggesting nuclear β-catenin could aid differential diagnosis of these subtypes. Mutations at S45, S33, S37 or T41 of CTNNB1 were found in only 50% of ACPs. Thus nuclear translocation of b-catenin occurs in the absence of CTNNB1 mutations, suggesting that other events can activate Wnt signalling in ACPs. We found mutations in 3 PCPs defined by classical morphological criteria. However, it is recognized that overlapping histological features with ACPs and Rathke’s cleft cyst may be seen in some presumed PCPs.
Loss of expression of E-cadherin is associated with invasion and metastasis in neoplasia. Previous reports show cleavage of E-cadherin and nuclear translocation of the cytoplasmic domain in other sellar tumours (6). We sought to determine whether E-cadherin cleavage occurs in CPs. No translocation was observed. Indeed, validation of the antibody used in previous reports (clone 36/E-cadherin) showed it to be non-specific to E-cadherin. In all cases, immunohistochemistry revealed no re-distribution of other adherens junction complex members (E-cadherin, α-catenin, p120 and plakoglobin) linked with β-catenin translocation.
We conclude that while mutations in exon 3 of b-catenin are seen in 50% of ACPs, nuclear β-catenin translocation occurs in all ACPs, suggesting that mutation is neither necessary nor sufficient for nuclear translocation. Redistribution of other adherens junction components is not linked with β-catenin translocation in ACP. Mutation in β-catenin may not be exclusive to ACPs.
Nothing to Disclose: VAP, SJL, RJC, BGR, NK, OA, AG
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