Endometrial Carcinoma: Pathology and Genetics
Moderator: Dr. Michael A. Wells
Section 3 -
Role of Beta-catenin in the Initiation and Progression of Endometrial Cancer
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.
- 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.