In the carcinogenesis of colorectal cancer (CRC) genetic instability and dysfunction of the Wnt-signalling pathway play important roles. Most Wnt-signalling dysfunctions lead to the nuclear accumulation of beta-catenin. The aim of the present study was to investigate whether nuclear accumulation of beta-catenin is associated with prognosis and genetic instability. We used immunohistochemistry to study nuclear beta-catenin expression in 67 CRCs. The expression was evaluated in the entire tumour section as mean values and in tumour budding at the invasive margin. We compared the results with chromosomal and microsatellite instability (CIN vs. MSI), p53 accumulation, and clinicopathological variables including survival. The nuclear accumulation of beta-catenin was significantly associated with abnormal p53 expression and aneuploidy, typically for CIN, whereas no tumour with nuclear beta-catenin expression at the invasive margin displayed MSI. The beta-catenin expression pattern did not correlate significantly with CRC patient prognosis when including all stages. However, in the clinically most interesting prognostic group, Dukes' stage B patients, high nuclear accumulation of beta-catenin was associated with a poor prognosis (p=0.01). Our results suggest that nuclear accumulation of beta-catenin in CRC is related to CIN and may be of prognostic importance. However, larger studies are needed to verify these findings.
"Approximately 60–80% of CRCs develop on the basis of an aberrant activation of the Wnt signaling pathway in which β-catenin serves as a central hub , . There are many reports about the prognostic significance of β-catenin in CRC , , , . Surprisingly, correlations between an immunohistochemically detected expression of β-catenin in CRC and prognosis are highly variable and contradictory. "
[Show abstract][Hide abstract] ABSTRACT: β-catenin plays a key role in the progression of colorectal cancer (CRC). However, its prognostic significance for patients with CRC remains controversial.
Identical search strategies were used to search relevant literatures in the PubMed, Embase and Web of Science databases. The correlation between β-catenin expression and clinicopathological features and prognosis was analyzed.
A total of 18 studies met the inclusion criteria, which comprised 3665 cases. Meta-analysis suggested that β-catenin overexpression in the nucleus was significantly associated with disease free survival (DFS) (n = 541 in 3 studies; HR = 1.87, 95% CI: 1.28-2.71; Z = 3.26; P = 0.001) and overall survival (OS) for CRC patients (n = 2630 in 10 studies; HR = 1.55, 95% CI: 1.12-2.14; Z = 2.62; P = 0.009). However, there was no significant association between β-catenin expression in the cytoplasm and OS (n = 1327 in 3 studies; HR = 1.04, 95% CI: 0.88-1.24, Z = 0.46, P = 0.643). The combined odds ratio (OR) of β-catenin in the nucleus indicated that β-catenin overexpression was associated with advanced stage CRC (n = 950 in 7 studies; OR = 0.71, 95% CI: 0.53-0.94; Z = 2.35; P = 0.019) and metastasis of CRC (n = 628 in 5 studies; OR = 0.49, 95% CI: 0.25-0.96, Z = 2.06, P = 0.039). β-catenin overexpression in the nucleus had no correlation with the tumor site (colon or rectum), differentiation grade, lymph node status or depth of invasion. The pooled ORs were 1.09 (95% CI: 0.41-2.91, Z = 0.18, P = 0.856), 1.27(95% CI: 0.76-2.10, Z = 0.92, P = 0.357), 0.71(95% CI: 0.46-1.09, Z = 1.58, P = 0.115) and 0.82(95% CI: 0.4-1.68, Z = 0.53, P = 0.594).
This study showed that β-catenin overexpression in the nucleus, rather than in the cytoplasm, appeared to be associated with progress disease and a worse prognosis for CRC patients.
PLoS ONE 05/2013; 8(5):e63854. DOI:10.1371/journal.pone.0063854 · 3.23 Impact Factor
"We observed b-catenin over-expression in >80% of our human TN breast cancer samples. Although all cells may not have apparent nuclear localization by IHC it is known that cytoplasmic accumulation of b-catenin is also an indicator for activated Wnt/b-catenin signalling and can predict survival outcome (Geyer et al, 2011; Khramtsov et al, 2010; Lugli et al, 2007; Martensson et al, 2007; Wong et al, 2003; Supporting Information Fig S8). Moreover, active gene transcription of a known direct target of canonical Wnt-signalling, AXIN2, by both ISH and IHC demonstrates transcriptional activation by b-catenin. "
[Show abstract][Hide abstract] ABSTRACT: Wnt/beta-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of beta-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active beta-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ER-alpha, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical beta-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/beta-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.
EMBO Molecular Medicine 02/2013; 5(1):1-16. DOI:10.1002/emmm.201201320 · 8.67 Impact Factor
"Beta-catenin overexpression was also associated with a reduced risk of death in the full cohort and in patients with stage III-IV disease, although these associations were weaker than for MSI status. Previous studies on beta-catenin as a prognostic marker have been conflicting, with some studies reporting a favourable or no prognostic value [14,35-38] and some an association with poor clinical outcome [12,13,39,40]. Many factors could explain the differing results regarding the prognostic value of beta-catenin overexpression; e.g. "
[Show abstract][Hide abstract] ABSTRACT: Despite their pivotal roles in colorectal carcinogenesis, the interrelationship and prognostic significance of beta-catenin alterations and microsatellite instability (MSI) in colorectal cancer (CRC) needs to be further clarified. In this paper, we studied the associations between beta-catenin overexpression and MSI status with survival from CRC, and with expression of p21, p27, cyclin D1 and p53, in a large, prospective cohort study.
Immunohistochemical MSI-screening status and expression of p21, p27 and p53 was assessed in tissue microarrays with tumours from 557 cases of incident CRC in the Malmö Diet and Cancer Study. Chi Square and Spearman’s correlation tests were used to explore the associations between beta-catenin expression, MSI status, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between beta-catenin overexpression, MSI status and cancer specific survival (CSS).
Positive MSI screening status was significantly associated with older age, female sex, proximal tumour location, non-metastatic disease, and poor differentiation, and inversely associated with beta-catenin overexpression. Beta-catenin overexpression was significantly associated with distal tumour location, low T-stage and well-differentiated tumours. Patients with MSI tumours had a significantly prolonged CSS in the whole cohort, and in stage III-IV disease, also in multivariable analysis, but not in stage I-II disease. Beta-catenin overexpression was associated with a favourable prognosis in the full cohort and in patients with stage III-IV disease. Neither MSI nor beta-catenin status were predictive for response to adjuvant chemotherapy in curatively treated stage III patients. P53 and p27 expression was positively associated with beta-catenin overexpression and inversely associated with MSI. Cyclin D1 expression was positively associated with MSI and beta-catenin overexpression, and p21 expression was positively associated with MSI but not beta-catenin overexpression.
Findings from this large, prospective cohort study demonstrate that MSI screening status in colorectal cancer is an independent prognostic factor, but not in localized disease, and does not predict response to adjuvant chemotherapy. Beta-catenin overexpression was also associated with favourable outcome but not a treatment predictive factor. Associations of MSI and beta-catenin alterations with other investigative and clinicopathological factors were in line with the expected.
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