Section 3 -

Role of Beta-catenin in the Initiation and Progression of Endometrial Cancer José Palacios

The Wnt signalling pathway plays an important role in normal and tumoral cells. In the absence of an extracellular Wnt signal in normal cells, the free (cytoplasmic) β-catenin level is low, since the protein is targeted for destruction in the ubiquitin-proteasome system after phosphorylation by glycogen synthase kinase-3β (GSK-3β). The latter forms a complex with adenomatous polyposis coli (APC) protein and other proteins, such as AXIN1, AXIN2 and protein phosphatase 2A (PP2A). The most common molecular alterations in tumour cells leading to disruption of β-catenin degradation are mutations that inactivate APC or activate β-catenin itself. These alterations produce an accumulation of cytoplasmic β-catenin that translocates into the nucleus and, interacting with members of the lymphoid enhancer factor-1/T-cell factor (Lef-1/Tcf), activates transcription of various genes, such as cyclin D1 and MYC. Regarding endometrial carcinomas, the Wnt signalling pathway is altered only in EEC. In these tumors, mutations of APC have not been detected (Schlosshauer et al 2000; Moreno-Bueno et al 2002), but β-catenin mutations occurred in approximately 15% to 20% of EEC (Fukuchi et al 1998; Mirabelli-Primdahl et al 1999; Schlosshauer et al 2000; Saegusa et al 2001; Moreno-Bueno et al 2002), and in 14% of atypical hyperplasia (Moreno-Bueno et al 1993). Most studies on β-catenin mutations have only analyzed the consensus sequence for GSK-3β phosphorylation in exon3. Mutations affect the amino acids implicated in the down-regulation of β-catenin through phosphorylation by this serine/threonine kinase (serine 33, serine 37, threonine 41and serine 45) and two adjacent residues. Mutations in these residues render a fraction of cellular β-catenin sensitive to APC-mediated down-regulation and are responsible for the up-regulation of cytoplasmic β-catenin and its accumulation in the nuclei of tumor cells, which can be detected by immunohistochemistry Around 15% of tumours featured β-catenin nuclear accumulation without evidence of β-catenin mutations, suggesting alterations in molecules of the Wnt pathway other than β-catenin mutations. However no APC, AXIN1 or AXIN2 mutations have been detected in EEC. In addition, alterations of genes involved in GSK-3β regulation, such as PTEN and KRAS, have also been excluded as causes of β-catenin up-regulation (Moreno-Bueno et al 2002). From a morphological point of view, several studies have stressed the association between nuclear β-catenin accumulation and squamous metaplasia in EEC. Although nuclear β-catenin may be associated with usual squamous metaplasia, it is more characteristic associated with morular metaplasia. In this sense, β-catenin mutations are found in 50% of AEH with squamous morules (Brachtel et al, 2005) . Some series have not found significant relationships between β-catenin gene mutation and clinicopathological features, such as age, grade and stage. However, other series have exhibited an association with low grade and absence of lymph node metastases (Saegusa et al., 2001), suggesting that b-catenin mutations might occur in a subset of less aggressive tumours. References Brachtel EF, Sanchez-Estevez C, Moreno-Bueno G, Prat J, Palacios J, Oliva E. Distinct molecular alterations in complex endometrial hyperplasia (CEH) with and without immature squamous metaplasia (squamous morules). Am J Surg Pathol 2005; 29:1322-1329. Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hirohashi S. Beta-catenin mutation in carcinoma of the uterine endometrium. Cancer Res 1998; 58:3526-3528. Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri C, Dale D, Holowaty E, Bapat B, Gallinger S, Redston M. Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res 1999; 59:3346-51. Moreno-Bueno G, Hardisson D, Sanchez C, Sarrio D, Cassia R, Garcia-Rostan G, Prat J, Guo M, Herman JG, Matias-Guiu X, Esteller M, Palacios J. Abnormalities of the APC/β-catenin pathway in endometrial cancer. Oncogene 2002; 21:7981-79 90. Moreno-Bueno G, Hardisson D, Sarrio D, Sanchez C, Cassia R, Prat J, Herman JG, Esteller M, Matias-Guiu X, Palacios J. Abnormalities of E- and P-cadherin and catenin ( b-, g-catenin, and p120ctn) expression in endometrial cancer and endometrial atypical hyperplasia. J Pathol 2003; 199:471-478. Saegusa M, Hashimura M, Yoshida T, Okayasu I. β-catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer. 2001; 84:209-217. Schlosshauer PW, Pirog EC, Levine RL, Ellenson LH. Mutational analysis of the CTNNB1 and APC genes in uterine endometrioid carcinoma. Mod Pathol 2000; 13:1066-1071.