Beta-catenin expression in relation to genetic instability and prognosis in colorectal cancer

ArticleinOncology Reports 17(2):447-52 · March 2007
DOI: 10.3892/or.17.2.447 · Source: PubMed
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.
    • "[30] Therefore, the disruption of Wnt/β-catenin signaling represents an opportunity for rational cancer chemoprevention and therapy. [30] In CRC, 90% of all tumors have a mutation in a key regulatory factor of the Wnt/β-catenin signaling pathway that results in pathway activation, and up to 80% of tumors exhibit nuclear accumulation of β-catenin.313233 "
    [Show abstract] [Hide abstract] ABSTRACT: Targeted drugs therapies that block the molecular pathways involved in the development and progression of gastro-intestinal (GI) cancers have recently gained considerable attention. In addition to agents targeting vascular endothelial growth factor (VEGF), epidermal growth factor receptor, the multi-kinase inhibitor, and regorafenib have also become available for the treatment of metastatic colorectal cancer patients. Currently, trastuzumab, an antibody targeting human epidermal growth factor receptor-2 (HER-2), in combination with cytotoxic drugs is considered as the standard treatment for patients with HER-2 positive gastric cancer (GC). The effi cacy of ramucirumab, a human monoclonal antibody that inhibits VEGF from binding to its receptor in GC, has also been recently demonstrated. At present, a great number of novel targeted drugs are in pre-clinical or clinical studies. In this review, we summarize trends in the use of molecularly targeted drugs that have proven to be effective for treating GI cancers, with a focus on emerging strategies for personalized treatment.
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    • "Approximately 60–80% of CRCs develop on the basis of an aberrant activation of the Wnt signaling pathway in which bcatenin serves as a central hub [34,35]. There are many reports about the prognostic significance of b-catenin in CRC [20,24,28,29] . Surprisingly, correlations between an immunohistochemically detected expression of b-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.
    Full-text · Article · May 2013
    • "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 InformationFig 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.
    Full-text · Article · Feb 2013
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