β‐catenin expression and claudin expression pattern as prognostic factors of prostatic cancer progression

Szász, Attila Marcell; Nyírády, Péter; Majoros, Attila; Szendrői, Attila; Szűcs, Miklós; Székely, Eszter; Tőkés, Anna Mária; Romics, Imre; Kulka, Janina

doi:10.1111/j.1464-410x.2009.08808.x

Cited by 24 publications

(15 citation statements)

References 24 publications

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“…It has been observed that β-Catenin expression and localization change during human prostate cancer progression, however, results are inconsistent. Several studies have seen an increase in β-Catenin expression and nuclear localization in late stage cancer samples, while others have reported a loss in nuclear expression in advanced tumours [12], [13], [14], [15], [16]. In addition to its role in WNT signalling, β-Catenin can act as a co-factor with AR, suggesting it has a role in castration-resistant disease.…”

Section: Introductionmentioning

confidence: 99%

β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma

et al. 2013

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Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans.

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Section: Introductionmentioning

confidence: 99%

β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma

et al. 2013

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“…These studies provide evidence for functional overlap between GLI1 and lipocalin 2 in breast cancer and, accordingly, the expression of both proteins is associated with the ER − phenotype [49], [50], [51], [52]. Similarly, although the tight junction protein claudin 1 (CLDN1) is often decreased in breast tumours [53], [54], [55], high expression has been described in ER − tumours [56], [57]. In the prostate, claudin1 expression is high in the basal layer of benign tissue and its expression decreases with increasing tumour aggressiveness [58], [59].…”

Section: Discussionmentioning

confidence: 95%

GLI1 Confers Profound Phenotypic Changes upon LNCaP Prostate Cancer Cells That Include the Acquisition of a Hormone Independent State

et al. 2011

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The GLI (GLI1/GLI2) transcription factors have been implicated in the development and progression of prostate cancer although our understanding of how they actually contribute to the biology of these common tumours is limited. We observed that GLI reporter activity was higher in normal (PNT-2) and tumourigenic (DU145 and PC-3) androgen-independent cells compared to androgen-dependent LNCaP prostate cancer cells and, accordingly, GLI mRNA levels were also elevated. Ectopic expression of GLI1 or the constitutively active ΔNGLI2 mutant induced a distinct cobblestone-like morphology in LNCaP cells that, regarding the former, correlated with increased GLI2 as well as expression of the basal/stem-like markers CD44, β1-integrin, ΔNp63 and BMI1, and decreased expression of the luminal marker AR (androgen receptor). LNCaP-GLI1 cells were viable in the presence of the AR inhibitor bicalutamide and gene expression profiling revealed that the transcriptome of LNCaP-GLI1 cells was significantly closer to DU145 and PC-3 cells than to control LNCaP-pBP (empty vector) cells, as well as identifying LCN2/NGAL as a highly induced transcript which is associated with hormone independence in breast and prostate cancer. Functionally, LNCaP-GLI1 cells displayed greater clonal growth and were more invasive than control cells but they did not form colonies in soft agar or prostaspheres in suspension suggesting that they do not possess inherent stem cell properties. Moreover, targeted suppression of GLI1 or GLI2 with siRNA did not reverse the transformed phenotype of LNCaP-GLI1 cells nor did double GLI1/GLI2 knockdowns activate AR expression in DU145 or PC-3 cells. As such, early targeting of the GLI oncoproteins may hinder progression to a hormone independent state but a more detailed understanding of the mechanisms that maintain this phenotype is required to determine if their inhibition will enhance the efficacy of anti-hormonal therapy through the induction of a luminal phenotype and increased dependency upon AR function.

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“…Our results suggested that patients with organ-confined (OCC) and advanced cancer (CAC) were subsets with distinct claudin expression profiles, specifically, claudin-4 and -5 was expressed at higher levels in PCa with poor prognosis [17]. Elevated membranous claudin-4 expression was described by others as well to be a marker of poor prognosis in prostate cancer [18].…”

Section: Introductionmentioning

confidence: 84%

Prognostic potential of ERG (ETS-related gene) expression in prostatic adenocarcinoma

et al. 2013

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Purpose Following patients after prostatectomy can be expensive and stressful, therefore, a novel and reliable approach to improve stratification is needed both at diagnosis of PCa and following its treatment. We evaluate the association of both ERG and claudin-4, -5 and betacatenin expression in tumor tissues of patients with organ confined and advanced prostatic adenocarcinomas. Methods A total of 30 patients were included in the study. Nine men, who underwent radical prostatectomy for organ confined (pT2N0M0) cancer (OCC); 11 patients with clinically advanced cancer (CAC); and 11 controls with benign prostatic hypertrophy (BPH). Using immunohistochemistry applied to tissue microarrays, each group was evaluated for beta-catenin, claudin-4, -5 and ERG expression. Results The expression of ERG was higher in the CAC group as compared to OCC and BPH (p = 0.7684, p = 0.0224, respectively). Among these patients, 5 from the CAC (45%) and 5 from the OCC group (56%) stained positively for ERG (p = 1.0). The mean staining score for those with ERG+ advanced cancer was greater than that for the ERG+ organ-confined cancer (p = 0.0209). ERG staining correlated with Gleason score (Pearson correlation: 0.498, p = 0.0051), but not with serum PSA level (Pearson correlation: 0.404, p = 0.1202). When analyzing outcome data high ERG expressing tumors have shown a significantly worse overall survival (p = 0.0084). Conclusions Our results of presence or absence of claudin-4 and -5 and ERG staining intensities suggest their potential as prognostic factors for prostate cancer.

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β‐catenin expression and claudin expression pattern as prognostic factors of prostatic cancer progression

Cited by 24 publications

References 24 publications

β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma

β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma

GLI1 Confers Profound Phenotypic Changes upon LNCaP Prostate Cancer Cells That Include the Acquisition of a Hormone Independent State

Prognostic potential of ERG (ETS-related gene) expression in prostatic adenocarcinoma

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