α-Catenin expression has prognostic value in local and locally advanced prostate cancer

Abstract

Normally functioning cell–cell adhesion plays an important role in the maintenance of tissue architecture and cell cohesion. E-cadherin is an important adhesion molecule of epithelial cells. In many types of cancer the expression of E-cadherin is reduced leading to increased risk of disease progression. α-Catenin is one of the intracellular elements of the E-cadherin–catenin complex. The abnormalities in the expression of α-catenin seem to associate with malignant cellular features and disease progression in prostate cancer. To further analyse the significance of α-catenin expression, we studied 215 cases of prostate cancer by immunohistochemistry and the results were related to other known prognostic factors and patient survival during a mean follow-up period of 13 years. α-Catenin expression was down-regulated in 19% of the cases and 3% of the tumours were totally α-catenin-negative. The abnormal α-catenin expression and cytoplasmic signal were significantly linked with high T-category, metastatic disease, high Gleason score, perineural growth, high mitotic rate, high S phase fraction and DNA aneuploidy ( P < 0.05 for all). In the survival analysis, reduced α-catenin expression ( P = 0.06) and cytoplasmic signal ( P = 0.04) were related to unfavourable patient outcome. In the multivariate analysis, including TM-classification and Gleason score, α-catenin expression had independent prognostic value in T1–2 M0 tumors. In the M0 tumours, abnormal α-catenin signal was independently associated with recurrence-free survival as well. The results indicate that down-regulation of α-catenin is related to several malignant cellular features, and it seems to have prognostic significance in the early phases of cancer progression. We suggest that α-catenin expression can provide prognostic information in early prostate cancer. © 1999 Cancer Research Campaign

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

“…We also provide evidence for a new level of WNT and β-catenin regulation of DNA damage via α-catenin. This is in agreement with numerous studies showing that gain-of-function mutations in β-catenin signaling and loss of α-catenin regulation are prevalent in cancer (Aaltomaa et al, 1999;Anttila et al, 1998;Clevers and Nusse, 2012;Gofuku et al, 1999;Lifschitz-Mercer et al, 2001;Matsui et al, 1994;Nakopoulou et al, 2002;Polakis, 2000;Richmond et al, 1997;Rimm et al, 1995;Shiozaki et al, 1994;Silvis et al, 2011;Tanaka et al, 2003;van Oort et al, 2007;Yang et al, 2006). This additional level of regulation by α-catenin may help explain why WNT stimulation has been reported to decrease the sensitivity of cells to DNA damage despite increased nuclear β-catenin levels (Chandra et al, 2015;Chen et al, 2007;Jun et al, 2016;Woodward et al, 2007), and why different experimental systems have had confounding results (Chevillard-Briet et al, 2014;Orford et al, 1999;Tao et al, 2015;Watson et al, 2010).…”

“…This junctional population of β-catenin may also be responsive to WNT signaling (Hendriksen et al, 2008), suggesting that crosstalk between WNT signaling and adhesion complexes can be mediated by β-catenin (McCrea et al, 2015). Inactivating mutations in α-catenin, activating mutations in β-catenin and changes in the expression levels of these proteins have been repeatedly tied to various cancers (Aaltomaa et al, 1999;Anttila et al, 1998;Gofuku et al, 1999;Lifschitz-Mercer et al, 2001;Matsui et al, 1994;Nakopoulou et al, 2002;Richmond et al, 1997;Rimm et al, 1995;Shiozaki et al, 1994;Silvis et al, 2011;Tanaka et al, 2003;van Oort et al, 2007).…”

Bench to bedside and back again: Molecular mechanisms of α-catenin function and roles in tumorigenesis

“…Although loss of α-catenin mRNA and protein in cancer cells can be attributed to epigenetic mechanisms of gene silencing, there are instances where loss of plasma membrane staining and subsequent cytoplasmic accumulation of α-catenin are associated with increased metastasis [59,60] and decreased patient survival [47,61,62]. The new model of α-catenin function posits that α-catenin conformation in the cytoplasmic pool is key to α-catenin function, rather than the membrane associated pool per se, since cytoplasmically localized α-catenin homodimers regulate actin and membrane dynamics (Figure 1, right).…”

Management of High-Risk Populations with Locally Advanced Prostate Cancer

“…Normally functioning cell-cell adhesion plays a central role in the maintenance of tissue architecture and cell cohesion [59]. E-cadherin is an important transmembrane protein with epithelial cell adhesion properties [60].…”