Expression Pattern Of Beta-catenin Research Articles

The correlation between beta-catenin expression pattern and adverse prognostic factors in a cohort of invasive breast carcinoma patients in Sri Lanka

Journal of Diagnostic Pathology is a peer reviewed journal published biannually by the College of Pathologists of Sri Lanka. The journal publishes manuscripts dealing with all aspects of pathology. The aim of the journal is to update knowledge and encourage original research in the field of pathology.

Alteration in key oncoprotein expression in gastric adenocarcinoma - An immunohistochemical study.

This study was conducted to evaluate the frequency and clinicopathologic correlates of human epidermal growth factor receptor 2 (HER-2)/neu and betacatenin (BC) oncoproteins in gastric adenocarcinoma and to seek correlation if any between their expression status. This cross-sectional analytical immunohistochemistry (IHC) study was performed on 50 cases of gastric adenocarcinoma. HER-2/neu immunoexpression was scored as per criteria by Ruschoff et al. as positive (3+), equivocal (2+), and negative (1+, 0). Aberrant BC expression was categorized as nuclear, cytoplasmic, and reduced membranous immunoexpression. Protein expression results of both oncoproteins were correlated with conventional clinicopathological parameters. Correlation between immunoexpression profiles of both proteins was also analyzed. P <0.05 was considered statistically significant. HER-2/neu positivity (2 + and 3+) was seen in 94% of the cases; almost 60% had strong (3+) expression. All cases showed aberrant BC immunoexpression (any pattern) except 2 cases that revealed negative expression (a form of aberrant immunoexpression) and were removed from analysis due to a very small number. The pattern of BC expression was as follows: nuclear expression (38%), cytoplasmic expression (82%), reduced membranous expression (96%), no staining (4%) cases. HER-2/neu expression correlated with age. No significant correlation was found between any of the 2 oncoprotein immunoexpression and other clinicopathological parameters (P > 0.05). Concordance between protein expression of HER-2/neu and BC was seen in >93% cases, however, the correlation was not significant. HER-2/neu and BC oncoprotein expression are frequently dysregulated in gastric adenocarcinomas. The significance of pathways involving HER-2/neu and BC in gastric carcinogenesis should be explored.

Subtype-dependent difference of glucose transporter 1 and hexokinase II expression in craniopharyngioma: an immunohistochemical study

Papillary craniopharyngiomas are characterized by the BRAF V600E mutation. Enhancement of glucose metabolism may be involved in the downstream of the BRAF V600E mutation in many types of tumors. Glucose metabolism was investigated in craniopharyngioma using immunohistochemical analysis. The study included 29 cases of craniopharyngioma (18 adamantinomatous type [ACP], 11 papillary type [PCP]). Immunohistochemical analysis was performed with anti-glucose transporter-1 (GLUT-1), anti-hexokinase-II (HK-II), anti-BRAF V600E, and anti-beta-catenin antibodies. Expressions of GLUT-1 and HK-II were evaluated using a semiquantitative 4-tiered scale as 0, 1+, 2+, 3+, and divided into negative (0 or 1+) or positive (2+ or 3+) group. GLUT-1 expression level was significantly higher in PCPs than ACPs (0, 1+, 2+, 3+ = 2, 12, 4, 0 cases in ACP, respectively, 0, 1+, 2+, 3+ = 0, 2, 5, 4 in PCP, p = 0.001), and most PCPs were classified into positive group (positive rate, 22.2% [4/18] in ACP, 81.8% [9/11] in PCP; p = 0.003). HK-II expression was also conspicuous in PCPs (0, 1+, 2+, 3+ = 7, 9, 2, 0 cases in ACP, 0, 3, 3, 5 in PCP; p = 0.001), and most of them divided into positive group (positive rate, 11.1% [2/18] in ACP, 72.7% [8/11] in PCP; p = 0.001). Expression patterns of BRAF V600E and beta-catenin reflected the clinicopathological subtypes. Both GLUT-1 and HK-II expressions were prominent in PCP. Glucose metabolism might be more enhanced in PCP than ACP. PCP may use the glucose metabolic system downstream of the BRAF V600E mutant protein.

Association of different patterns of expression of beta-catenin and cyclin D1 with pathogenesis of breast carcinoma.

Beta-catenin and cyclin D1 have attracted considerable attention in recent studies as potential proto-oncogenes in many human cancers especially colonic cancer. Beta-catenin plays multiple roles within the cell such as canonical Wnt signaling where cyclin D1 has been identified as one of its target genes. The role of beta-catenin and cyclin D1 in breast cancer has been evaluated in many studies but not established yet. The expression of beta-catenin and cyclin D1 was evaluated in 82 cases of breast carcinoma (BCa) and 32 cases of ductal carcinoma in situ(DCIS) by immunohistochemistry (IHC). Their relationship with clinicopathological features was also investigated. Statistical analysis was done to establish an association. Abnormal expression of beta-catenin (ABE) was seen in 80.2% cases of invasive ductal carcinoma (IDC) and 47% cases of DCIS, while the cyclin D1 positive expression rate was 60.9% and 50%, respectively. In the cases showing ABE, cyclin D1 positivity was 88.1%. ABE showed significant association with high-grade BCa. The most common pattern of ABE was loss of membrane with nuclear positivity which is associated with worst prognosis. In addition, ABE in cases of BCa and DCIS showed concordant patterns. Therefore, an association exists between ABE and cyclin D1 in BCa and its precursor lesions implying that Wnt/beta-catenin oncogenic pathway may have a definite role in breast carcinogenesis and can be used for targeted therapy. Also, different patterns of beta-catenin expression may have prognostic and predictive value.

Low endometrial beta-catenin and cadherins expression patterns are predictive for primary infertility and recurrent pregnancy loss

Inadequate uterine receptivity is responsible for two-third of implanting failures. Aim of the study was to investigate the role of epithelial adherence and tight-junction molecules expressed by human endometrium in predicting womens’ fertility outcome. A total of 76 consecutive women, including 24 fertile (G1), 40 primary infertile (G2), and 12 recurrent pregnancy loss (RPL, G3) women, who underwent diagnostic hysteroscopy plus endometrial biopsy between 2005 and 2016 at the Gynecology Division of Sant’Andrea Hospital, Sapienza University of Rome, in Italy, were retrospectively identified and included into the study. Endometrial biopsies were assessed for the immunohistochemical expression of beta-catenin (β-catenin), E-cadherin and K-cadherin biomarkers. Expression profiles were compared between the three groups of patients and were correlated with patients’ fertility outcome. In infertile patients there was a significant lower endometrial expression of β-catenin (p = .001), E-cadherin (p = .001) and K-cadherin (p = .002), compared to the fertile ones. Furthermore, β-catenin and E-cadherin intensity gradients of expression at glandular level were found totally reversed in infertile patients. Significant lower expression levels of K-catenin (p = .016) and E-cadherin (p < .0001) at glandular level were found in RPL patients. Results showed that the low endometrial expression of β-catenin, E-cadherin and K-cadherin were associated to fertility-related problems, such as primary intertility and RPL.

Shadow Cell Differentiation: A Comparative Analysis of Modes of Cell Death with Apoptosis and Epidermal/Trichilemmal Keratinization

Shadow cells are characterized by an eosinophilic cytoplasm and a ghost-like nuclear contour; the cell shape is preserved, in spite of nuclear disappearance. Shadow cell nests (SCNs) are frequently observed in pilomatricoma (PMX), where the transitional cells immediately adjacent to SCNs often have a crescent-shaped nucleus showing fragmentation similar to that of apoptotic bodies. They show nuclear accumulation of beta-catenin and DNA double strand breaks (as revealed by in situ 3′-tailing reaction or immunohistochemistry for single-stranded DNA [ssDNA]), while they are negative for cleaved caspase-3 or cleaved lamin A, suggesting that shadow cell differentiation (SCD) is a caspase-independent programmed cell death. SCD can be differentiated from epidermal keratinization (EK) and trichilemmal keratinization (TK) based on the expression pattern of beta-catenin, ssDNA, and caspase-14/CD138. SCD is observed not only in PMX, but also sometimes in basal cell carcinomas, gonadal teratomas, and various extra-cutaneous carcinomas. In particular, SCNs are found in 24% of endometrial adenoacanthoma and are derived from squamoid morules. This establishes a link between basaloid cells in PMX and squamoid morules in endometrial adenoacanthomas as common precursors of shadow cells. Overall, it is suggested that SCD is different from, but partly similar to, apoptosis and that SCD and EK/TK should be differentiated from the standpoint of cell death/differentiation.

Abstract 3904: Rspondin-1 contributes to tumor cell proliferation via Wnt signaling pathway

Abstract Diabetes mellitus and pancreatic cancer have long been considered to be clinically related to each other. Despite the ample epidemiological evidences indicating relevance between two major human diseases, the precise mechanism to link both of these diseases are still unclear. We demonstrated altered beta-catenin and Wnt3a protein expression in pancreas of diabetic mouse in age-dependent manner, which indicates the chronic diabetic condition may contribute to the pancreatic cancer progression of peri-islet region through elevated Wnt signaling. We also identified the altered expression level of Rspondin-1, secreted agonist of Wnt signaling pathway, in in vivo diabetic mouse model, which showed a similar expression pattern of Wnt3a and beta-catenin. Finally we demonstrated the effect of in vitro diabetic condition on Rspondin expression level of mouse pancreatic beta cell(Min6) and pancreatic cancer cell lines(Panc-1, AsPc-1). The expression level of Rspondin-1 was down-regulated in Min6 cells cultured in high glucose condition, whereas up-regulated in pancreatic cancer cells cultured in in vitro diabetic condition, which correlates with in vivo Rspondin-1 expression study. These results provide new insights about the Wnt signaling and related proteins as molecular linkers of chronic diabetes and pancreatic cancer. Citation Format: So Hyun Park, Sol Kim, Min Yeong Choi, Jiwoon Park, Shinae Kang, Hak-Zoo Kim. Rspondin-1 contributes to tumor cell proliferation via Wnt signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3904. doi:10.1158/1538-7445.AM2015-3904

Dysregulation of the beta-catenin complex as an independent predictor of oncological outcomes in patients with ccRCC.

493 Background: Epithelial to mesenchymal transition (EMT) is thought to play a crucial role in cancer progression and development of metastasis. Thus, we evaluated dysregulation of beta-catenin as a part of EMT and its clinical implications in patients with clear cell renal cell carcinoma (ccRCC). Methods: Immunohistochemical staining was performed for beta-catenin on tissue microarrays of patients with ccRCC. Membranous and cytoplasmatic beta-catenin expression patterns were assessed separately. Beta-catenin was considered normal if none or only one component was abnormal and was considered dysregulated if both components were abnormal. Differences in pathological characteristics between both groups were investigated. Differences in recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with the Kaplan-Meier method. Uni- and multivariate Cox proportional hazard models were used to assess independent predictors of oncological outcomes. Results: 406 patients with a median follow-up of 58 months were included. Overall, 52 (12.8%) and 25 (6.2%) patients recurred and died of ccRCC. Beta-catenin was dysregulated in 70 (17.2%) patients. Dysregulation of beta-catenin was significantly associated with adverse pathologic features, such as higher T-stage, nodal positivity, higher grade, presence of tumor thrombus, sarcomatoid features, necrosis and LVI (all p&lt;0.001). Patients with dysregulated beta-catenin had inferior RFS and CSS (both p&lt;0.001). In multivariate analysis adjusting for tumor stage, nodal status and grade, dysregulation of beta-catenin was an independent predictor of RFS (HR 2.2, 95%CI 1.2-3.9, p=0.008) and CSS (HR 2.4, 95%CI 1.1-5.6, p=0.044). Conclusions: Our results indicate that dysregulation of beta-catenin may be an important phenomenon in ccRCC carcinogenesis. These findings support further study of beta-catenin and systematic assessment of EMT in ccRCC.

E-cadherin, beta catenin, EGFR and cylin D1 expression in nasopharyngeal carcinoma in nigerians and correlation with stage at presentation and possible long term prognosis

Aim To determine the pattern of expression of selected bio-markers in nasopharyngeal carcinoma (NPC) and correlate it with stage at presentation and prognosis Methods In a prospective study, formalin fixed paraffin embedded (FFPE) tumour tissues from patients with NPC were stained using immunohistochemistry (IHC) for selected bio-markers, namely E-cadherin, beta catenin, EGFR and cyclin D1 Results Forty patients were included in the analysis and had IHC. Age ranged from 17-65 years with a mean age of 48 years. About 80% of our cases had TNM stage III while the rest had stage IV disease at presentation. Also all our cases were either WHO histologic type III or IV tumours. Beta catenin expression was present in about 50% of patients. E-cadherin expression was present in all cases in about 50-60% of tumour cells. Cyclin-D1 was also present in all cases in 20-30% of tumour cells. EGFR expression was strong and in a minimum of 70% of tumour cells in all cases. Conclusion The expression pattern of E-cadherin, beta catenin, EGFR and cyclin D1 in this study correlates with accelerated progression, early metastasis, advanced disease and high probability of local recurrence even after radiotherapy and chemotherapy.

Nuclear localization of beta-catenin in the nail matrix cells and onychomatricoma

Beta-catenin plays an important role in hair morphogenesis. Previously, nuclear localization of beta-catenin in hair matrix cells was found. Hair and nail have similar properties. However, the expression pattern of beta-catenin in the nail unit has not been reported yet. In this study we evaluated the expression pattern of beta-catenin in human nail unit and a rare nail tumor onychomatricoma.Normal human nail unit was obtained during polydactyly operations and cadavers. Immunohistochemistry for beta-catenin was applied to the sections of normal nail unit and onychomatricoma.

Expression of Dickkopf-1 and Beta-Catenin Related to the Prognosis of Breast Cancer Patients with Triple Negative Phenotype

Background and AimWe investigated the prognostic importance of dickkopf-1(DKK1) and beta-catenin expression in triple negative breast cancers.MethodsThe expression of DKK1 and beta-catenin was evaluated in breast cell lines using RT-PCR and western blot. Immunohistochemistry was used to characterize the expression pattern of DKK1 and beta-catenin in 85 triple negative breast cancers and prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression modeling.ResultsThe expression of DKK1 was confirmed in hormone-resistant breast cell lines MDA-MB-231, MDA-MB-231-HM and MDA-MB-435. Expression of DKK1 in triple negative breast cancers correlated with cytoplasmic/nuclear beta-catenin (p = 0.000). Elevated expression of DKK1 and cytoplasmic/nuclear beta-catenin in triple negative cancers indicate poor outcome of patients. DKK1 was also a prognostic factor for patients with earlier stage or no lymph node metastasis.ConclusionDKK1 together with beta-catenin might be important prognostic factors in triple negative breast carcinoma. DKK1 might be a valuable biomarker in predicting the prognosis of patients with earlier stage or no lymph node metastasis. It is possible that through further understanding of the role of Wnt/beta-catenin pathway activation, beta-catenin would be a potential therapeutic target for the triple negative breast cancer.

Modeling pattern formation in hydra: a route to understanding essential steps in development

Modeling of pattern formation in hydra has revealed basic mechanisms that underlie the reproducible generation of complex and self-regulating patterns. Organizing regions can be generated by a local self-enhancing reaction that is coupled with an inhibitory effect of longer range. Such reactions enable pattern formation even in an initially almost homogeneous assembly of cells. A long-ranging feedback of the organizer onto the competence to perform the pattern-forming reaction stabilizes the polar axial pattern during growth and allows for regeneration with preserved polarity. Hypostome formation is assumed to be under the control of two positive feedback loops in which Wnt3 is a common element. In addition to the well-established loop employing beta-catenin, a second cell-local loop is involved, possibly with Brachyury as an additional component. This model accounts for the different expression patterns of beta-catenin and Wnt3. Wnt molecules are proposed to play a dual role, functioning as activators and, after processing, as inhibitors. Since Wnt genes code for complete pattern-forming systems, gene duplication and diversification lead to a family of genes whose expression regions have a precise relation to each other. Tentacle formation is an example of positioning a second pattern-forming system by medium-ranging activation and local exclusion exerted by the primary system. A model for bud formation suggests that a transient pre-bud signal is involved that initiates the formation of the foot of the bud, close to the normal foot, as well as close to the bud tip. Many dynamic regulations, as observed in classical and molecular observations, are reproduced in computer simulations. A case is made that hydra can be regarded as a living fossil, documenting an evolutionary early axis formation before trunk formation and bilaterality were invented. Animated simulations are available in the supplementary information accompanying this paper.

Prognostic significance of claudin expression changes in breast cancer with regional lymph node metastasis

Adherent and tight junction molecules have been described to contribute to carcinogenesis and tumor progression. Additionally, the group of claudin-low tumors have recently been identified as a molecular subgroup of breast carcinoma. In our study, we examined the expression pattern of claudins, beta-catenin and E-cadherin in invasive ductal (IDCs) and lobular (ILCs) carcinomas and their corresponding lymph node metastases (LNMs). Tissue microarrays of 97 breast samples (60 invasive ductal carcinomas, 37 invasive lobular carcinomas) and their corresponding LNMs have been analyzed immunohistochemically for claudin-1, -2, -3, -4, -5, -7, beta-catenin and E-cadherin expression. The stained slides were digitalized with a slide scanner and the reactions were evaluated semiquantitatively. When compared to LNMs, in the IDC group beta-catenin and claudin-2, -3, -4 and -7 protein expression showed different pattern while claudin-1, -2, -3, -4 and -7 were differently expressed in the ILC group. Lymph node metastases developed a notable increase of claudin-5 expression in both groups. Decrease or loss of claudin-1 and expression of claudin-4 in lymph node metastases correlated with reduced disease-free survival in our patients. According to our observations, the expression of epithelial junctional molecules, especially claudins, is different in primary breast carcinomas compared to their lymph node metastases as demonstrated by immunohistochemistry. Loss of claudin junctional molecules might contribute to tumor progression, and certain claudin expression pattern might be of prognostic relevance.

Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development

Germ cells are the foundation of an individual, since they generate the gametes and provide the unique genome established through meiosis. The sex-specific fate of the germline in mammals is thought to be controlled by somatic signals, which are still poorly characterized. We demonstrate here that somatic Wnt signalling is crucial for the control of female germline development. Wnt-4 maintains germ cell cysts and early follicular gene expression and provides a female pattern of E-cadherin and beta-catenin expression within the germ cells. In addition, we find that Stra8 expression is downregulated and the Cyp26b1 gene is expressed ectopically in the partially masculinized Wnt-4-deficient ovary. Wnt-4 may control meiosis via these proteins since the Cyp26b1 enzyme is known to degrade retinoic acid (RA) and inhibit meiosis in the male embryo, and Stra8 induces meiosis in the female through RA. Reintroduction of a Wnt-4 signal to the partially masculinized embryonic ovary, in fact, rescues the female property to a certain degree, as seen by inhibition of Cyp26b1 and induction of Irx3 gene expression. Wnt-4 deficiency allows only 20% of the germ cells to initiate meiosis in the ovary, whereas meiosis is inhibited completely in the Wnt-4/Wnt-5a double mutant. These findings indicate a critical role for Wnt signalling in meiosis. Thus, the Wnt signals are important somatic cell signals that coordinate presumptive female follicle development.

Proteomic Profiling of Breast Carcinomas Based on Claudin Expression Pattern.

Abstract INTRODUCTION. With the advent of molecular techniques, the UNC workgroup (Perou 2000) has identified at least five biologically distinct subtypes (luminal A, luminal B, Her2+, triple-negative, normal-like) with genomic characterization of human breast tumors. The same lab (Herschkowitz 2007) identified a new and rare molecular subtype of human breast cancer which is now being referred to as the claudin-low subgroup. In our study, we aimed to perform a thorough analysis of the claudin, beta-catenin and E-cadherin protein expression pattern in invasive ductal (IDCs) and lobular (ILCs) breast carcinomas of different grades, their corresponding lymph node metastases (LNMs) and normal adjacent tissues NATs). METHODS. Tissue microarrays of 98 samples (59 IDCs: 20 grade 3, 26 grade 2 and 13 grade 1; 39 ILCs: 8 grade 3, 24 grade 2 and 7 grade 1), their corresponding LNMs and NATs have been analyzed immunohistochemically for beta-catenin, claudin-1, -2, -3, -4, -5, -7 and E-cadherin expression. The stained slides were digitalized with a slide scanner and the reactions were evaluated semiquantitatively according to our previous practice (Kulka 2009). RESULTS. Based on our evaluation, we were able to conclude the following significant results: 1) There is a markedly different expression of beta-catenin, claudin-1, -3, -4 and -7 in normal and neoplastic tissues. 2) Claudin-1, -2 and E-cadherin are able to differentiate ductal and lobular invasive carcinomas. 3) In E-cadherin-negative IDCs beta-catenin and claudin-7 is expressed on lower levels than in the E-cadherin-positive IDCs. In E-cadherin-positive ILCs the beta-catenin, claudin-4 and -7 is expressed at higher levels than in E-cadherin-negative ILCs. 4) Claudin-1 and -2 protein expression in the molecular subtypes can also distinguish luminal subtypes from each other and the HER2+ and triple-negative group. 5) Claudin-3 and E-cadherin or claudin-4 and -7 are both able to separate a claudin-low subtype of tumors with confidence.This later subclass also expresses beta-catenin on a lower level than the others. 6) Hierarchical clustering of primary carcinomas based on claudin expression reflects proliferation rates of the primary tumors. 7) Beta-catenin, claudin-1, -2 can differentiate primary carcinomas and lymph node metastases. 8) Histological grade correlates with claudin-1, -4 and -7 expression. CONCLUSION. According to our observations, the expression of TJ molecules, especially claudins, are different in tumors compared to normal breast tissue. Also, we could identify a claudin-low tumor subtype based on the loss of claudin-4 and -7 expression. Certain claudins are also differently expressed in the lymph node metastases as demonstrated by immunohistochemistry. Claudin profile of breast tumors correlates with histopathological variables and most likely it reflects an important mechanism of cancer differentiation and progression. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6123.

The intratumoral distribution of nuclear β‐catenin is a prognostic marker in colon cancer

Most colon cancers harbor mutations of APC or beta-catenin, both of which may lead to nuclear beta-catenin accumulation in the tumor cells and constitutively activated expression of its target genes. In many colon cancers, however, nuclear beta-catenin accumulation is heterogeneous throughout the tumor and often confined to the tumor margin. Herein, the authors investigated whether the intratumoral distribution of nuclear beta-catenin can serve as a prognostic marker for survival and tumor progression of stage IIA colon cancer patients. In total, 142 patients with primarily resected, moderately differentiated stage IIA colon cancer were included in this study. The patterning of nuclear beta-catenin expression was evaluated on immunohistochemically stained whole tissue sections of the tumors and was correlated with cancer-specific survival and disease-free survival using univariate and multivariate statistical analyses. Four distinct patterns of nuclear beta-catenin expression were identified, and 2 main categories comprising tumors with or without intratumoral regulation of nuclear beta-catenin were distinguished. Moreover, the results demonstrated that the patterning, and especially the regulation or absence of regulation of nuclear beta-catenin expression, was a strong predictive marker of patient survival and tumor progression. The current results indicated that the distribution of nuclear beta-catenin expression can be used as a good prognostic marker in patients with stage IIA colon cancer. Thus, the evaluation of nuclear beta-catenin may help to identify patients who will have a shorter than average survival and patients with a greater risk of disease progression who may be considered for adjuvant therapeutic modalities and intensified clinical aftercare in the future.

Inverse correlation of the up‐regulation of FZD10 expression and the activation of β‐catenin in synchronous colorectal tumors

We investigated the immunohistochemical expression patterns of Frizzled homolog 10 (FZD10), a cell-surface receptor for molecules in the Wnt pathway, in tissue samples derived from 104 patients with colorectal cancers (CRCs). There was no immunoreactivity for FZD10 in normal colonic mucosa, and only tumor cells in polyps and CRC tissues showed spotted immunostaining patterns in apical sides of the cytoplasm. In metastatic liver lesions, tumor cells showed cytoplasmic immunostaining similar to primary lesions, whereas normal liver parenchyma showed almost no immunostaining. Frequencies of FZD10-immunopositive cells in tumor tissues were significantly higher in CRCs than those in polyps (3.3 +/- 10.3% vs 20.5 +/- 31.7%, P = 0.0016), and almost equivalent with those in metastatic liver lesions (33.2 +/- 39.7% vs 26.4 +/- 33.4%, P = 0.133). Analyses of paired samples (polyps and CRCs, or CRCs and metastatic liver lesions from the same patient) suggested that a subset of CRCs possessed intrinsic genetic mechanisms causing the evolution of FZD10-positive clones during tumor progression, making FZD10 a promising candidate for molecular imaging and a target for therapy. To our surprise, cancer cells immunopositive for FZD10 showed significantly less nuclear accumulation of beta-catenin, compared to FZD10-immunonegative cancer cells, and there was a strong inverse correlation between nuclear immunostaining scores for beta-catenin expression and expression patterns of FZD10 (P = 0.0002), suggesting that FZD10 has a distinct role from other FZDs in canonical Wnt signal transduction.

Elevated expression of DKK1 is associated with cytoplasmic/nuclear β-catenin accumulation and poor prognosis in hepatocellular carcinomas

To assess the value of Dickkopf-1 (DKK1) for predicting clinical outcome of human hepatocellular carcinoma (HCC) in patients with HCC. Expression of DKK1 and beta-catenin was investigated in HCC cell lines using qRT-PCR, Western blotting and immunofluorescence. Tissue microarrays representing 314 HCC patients were used to determine the expression patterns of DKK1 and beta-catenin by immunohistochemistry, and prognostic significance was assessed by using Kaplan-Meier survival estimates and log-rank tests. The expression level of DKK1 was associated with the staining pattern of beta-catenin in HCC cell lines, and DKK1 overexpression correlated with beta-catenin cytoplasmic/nuclear accumulation in clinical HCC samples (P=0.011, correlation coefficient=0.144). High DKK1 expression predicted unfavorable prognosis in HCC patients, especially in early stage patients and those with normal AFP levels. In multivariate analyses, DKK1 was an independent predictor for overall survival (OS) (P=0.002) and disease-free survival (DFS) (P=0.002) of HCC patients. Furthermore, the HCC patients with high DKK1 expression and cytoplasmic/nuclear beta-catenin accumulation had very poor prognosis. Elevated expression of DKK1 is a critical event in patients with HCC that indicates poor clinical outcome. DKK1, alone or combined with beta-catenin, is a novel prognostic predictor for HCC patients.

β-catenin expression pattern in primary oral squamous cell carcinoma

Beta-catenin, a 92 kDa protein that binds to the cytoplasmic tail of E-cadherin, has an essential role in intercellular adhesion and signal transduction. Aberrant expression of beta-catenin has been associated with progression and metastasis of various human cancers. The aim of this study was to elucidate the expression pattern of beta-catenin in primary oral squamous cell carcinoma and examine the correlation between beta-catenin expression and tumor differentiation, histological grade and lymph node status as well as its clinical significances. Seventy-six patients with oral squamous cell carcinoma and sixteen metastatic lymph nodes were studied. The beta-catenin expression was determined by immunohistochemical staining. The correlation with clinical, histological data was analyzed statistically. Normal oral epithelium showed strong beta-catenin expression at the cell membrane, but no cytoplasmic or nuclear expression. Different degrees of reduced expression of beta-catenin at the cell membrane were found in 54 cases with squamous cell carcinoma (71%). Cytoplasmic beta-catenin expression was found in 17 tumors (22.4%). Three cases were found with nuclear beta-catenin expression. In sixteen lymph nodes with metastatic squamous cell carcinoma, negative beta-catenin expression at the cell membrane was seen in 13 tumors (81.2%) and weak expression in 3 tumors (18.8%). Statistical analysis showed that there was an inverse correlation between beta-catenin expression and lymph node status and histological grade of tumors. Reduced beta-catenin expression at the cell membrane is clearly associated with lymph node metastasis. A reduced expression of beta-catenin may constitute a hallmark of aggressive biological behavior of squamous cell carcinoma.

5α‐androstane‐3α,17β‐diol supports human prostate cancer cell survival and proliferation through androgen receptor‐independent signaling pathways: Implication of androgen‐independent prostate cancer progression

Androgen and androgen receptor (AR) are involved in growth of normal prostate and development of prostatic diseases including prostate cancer. Androgen deprivation therapy is used for treating advanced prostate cancer. This therapeutic approach focuses on suppressing the accumulation of potent androgens, testosterone and 5alpha-dihydrotestosterone (5alpha-DHT), or inactivating the AR. Unfortunately, the majority of patients with prostate cancer eventually advance to androgen-independent states and no longer respond to the therapy. In addition to the potent androgens, 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), reduced from 5alpha-DHT through 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs), activated signaling may represent a novel pathway responsible for the progression to androgen-independent prostate cancer. Androgen sensitive human prostate cancer LNCaP cells were used to compare 5alpha-DHT and 3alpha-diol activated androgenic effects. In contrast to 5alpha-DHT, 3alpha-diol regulated unique patterns of beta-catenin and Akt expression as well as Akt phosphorylation in parental and in AR-silenced LNCaP cells. More significantly, 3alpha-diol, but not 5alpha-DHT, supported AR-silenced LNCaP cells and AR negative prostate cancer PC-3 cell proliferation. 3alpha-diol-activated androgenic effects in prostate cells cannot be attributed to the accumulation of 5alpha-DHT, since 5alpha-DHT formation was not detected following 3alpha-diol administration. Potential accumulation of 3alpha-diol, as a result of elevated 3alpha-HSD expression in cancerous prostate, may continue to support prostate cancer growth in the presence of androgen deprivation. Future therapeutic strategies for treating advanced prostate cancer might need to target reductive 3alpha-HSD to block intraprostatic 3alpha-diol accumulation.