This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stefansson, I. M. Articles by Akslen, L. A. Search for Related Content PubMed PubMed Citation Articles by Stefansson, I. M. Articles by Akslen, L. A.

Prognostic Impact of Alterations in P-Cadherin Expression and Related Cell Adhesion Markers in Endometrial Cancer

From the Department of Pathology, the Gade Institute, and the Department of Obstetrics and Gynecology, University of Bergen, Haukeland University Hospital, Bergen, Norway.

Address reprint requests to Lars A. Akslen, MD, PhD, Department of Pathology, the Gade Institute, Haukeland University Hospital, Bergen, Norway; e-mail: lars.akslen{at}gades.uib.no

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Reduced tumor cell adhesion is associated with invasive growth and unfavorable prognosis. In endometrial carcinoma, the prognostic impact of adhesion markers (E-cadherin, beta-catenin [ß-catenin], P-cadherin, and p120^ctn) is partly unknown. We wanted to examine the expression pattern and prognostic value of these molecules in a population-based series of endometrial carcinoma patients.

PATIENTS AND METHODS: All patients diagnosed with endometrial carcinoma between 1981 and 1990 in Hordaland County, Norway, were included. Paraffin-embedded tumor tissue was available for 96% of the patients (n = 286), and was studied immunohistochemically for expression of E-cadherin, ß-catenin, P-cadherin, and p120^ctn. The tissue microarray technique was used for P-cadherin and p120^ctn. Median follow-up time for survivors was 9 years (range, 4 to 16 years) and follow-up was complete.

RESULTS: Pathologic expression of P-cadherin, E-cadherin, and ß-catenin was associated with a majority of the clinicopathologic variables. In univariate survival analyses, all adhesion markers influenced survival significantly (P < .05). Tumors with pathologic expression of both E-cadherin (low expression) and P-cadherin (high expression; 19%), and ß-catenin (low expression) and P-cadherin (high expression; 16%), had significantly reduced survival compared with the remaining samples (P < .001 for both). In multivariate models, all markers except E-cadherin showed independent prognostic significance in addition to the traditional tumor features.

CONCLUSION: Differential expression of P-cadherin and ß-catenin seems to be important in endometrial carcinoma and is associated with aggressive subgroups. Our findings also indicate that a shift from E-cadherin to P-cadherin expression (cadherin switch) is an important prognostic feature in these tumors.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Endometrial carcinoma is among the most common malignancies of the female genital tract in Western countries, with several well-established prognostic factors.^1–3 Still, especially for patients with localized tumors, identification of additional prognostic markers is important for a better detection of patients with high risk of relapse or death from the disease.

Alterations in cellular adhesion molecules are important for the development of invasion and metastatic capacity in human cancers.⁴ Among these, cadherins represent a group of Ca-dependent cell surface molecules, and to date, E-cadherin is the best known.^5,6 Altered E-cadherin expression has been related to a more infiltrative growth pattern in cancers of the breast,^7,8 stomach,⁹ lung,¹⁰ large bowel,¹¹ and prostate.¹² In endometrial carcinoma, studies have shown an association between reduced or absent E-cadherin expression and high International Federation of Gynecology and Obstetrics (FIGO) grading system, deep myometrial invasion, risk of tumor recurrence, and metastatic disease.^13–17

The intracellular domain of E-cadherin connects to the actin cytoskeleton via the catenins.⁴ In addition to this role, beta-catenin (ß-catenin) activates the Wingless-Wnt (Wnt) signaling pathway, acting as an oncogene.¹⁸ Mutations in the ß-catenin gene (CTNNB1) have been reported in 14% to 44% of endometrial carcinomas,^19–21 but none of these studies have focused on the prognostic relevance of altered ß-catenin expression. Another component of this complex, catenin p120^ctn, also binds to the cytoplasmic tail of E-cadherin.²² Alterations of p120^ctn seem to be frequent in human tumors,^23–26 and loss of or reduced expression has been associated with poor prognosis.^27–29 In endometrial carcinomas, one small study reported a different cellular distribution of p120^ctn in well-differentiated compared with poorly differentiated tumors,³⁰ whereas a recent study found no difference between endometrioid and nonendometrioid subtypes.³¹ To our knowledge, the prognostic relevance of p120^ctn has not been studied previously in endometrial tumors.

P-cadherin is expressed in the basal layers of stratified epithelia, indicating a role in cell growth and differentiation.³² Its expression pattern has been linked to a more dedifferentiated stem-cell-related population of tumor cells,³² although the importance of P-cadherin in different tumors is not well understood. A few studies on breast cancer have reported upregulation as an indicator of poor survival.^33,34 P-cadherin is normally expressed in the endometrium,³⁵ and upregulation was found in nonendometrioid carcinomas in one series.³¹ Patient survival or other clinicopathologic associations have not been examined previously.

The aim of this study was to investigate the expression patterns and prognostic significance of the cellular adhesion markers E-cadherin, P-cadherin, ß-catenin, and p120^ctn, within a well-defined population-based series of endometrial carcinoma, with complete follow-up.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Patients
All patients diagnosed with endometrial carcinoma in Hordaland county, Norway, in the 10-year period 1981 to 1990 have been studied. Hordaland county has approximately 400,000 inhabitants, representing approximately 10% of the total population of Norway, and has a similar age-adjusted incidence rate of endometrial cancer.³⁶ The treatment protocol was constant during this study period, and consisted of abdominal hysterectomy with bilateral salpingo-oophorectomy as initial treatment. Adjuvant radiation therapy was recommended for all patients with myometrial tumor infiltration without distant metastases. Intravaginal radiation was given to patients with highly or moderately differentiated tumors infiltrating less than half of the myometrium. For the remaining patients, external radiation to the pelvis (50 Gy) was recommended. For some patients, however, older age or intercurrent disease resulted in less aggressive treatment, and gestagens were given as part of the primary treatment to some of these patients. The Norwegian Data Inspectorate and the Regional Ethical Committee, Health Region III, approved the research.

Paraffin-embedded tumor tissue, available in 96% of the total population (n = 286), was studied, and original microscopic slides were reviewed by one pathologist (I.M.S.). All patients were staged retrospectively according to the FIGO 1988 criteria,³⁷ and the following histologic characteristics were recorded: histologic type; FIGO grade in accordance with established criteria;³⁸ nuclear grade according to Zaino;³⁹ solid growth, necrosis, and growth pattern according to Lax;⁴⁰ myometrial infiltration, measured as less than or equal to versus more than half of the myometrial thickness; vascular invasion, recorded as no invasion, tumor tissue in one vascular space, or in more than one vascular space; and mitotic count, recorded as the number of mitoses in 10 high-power fields (x400), examined within the most active area.

Follow-Up
The median follow-up period for the survivors was 9 years (range, 4 to 16 years). None of the information from patients was lost because of insufficient follow-up data. Information about survival was obtained from medical records, the Cancer Registry of Norway, and the Registry of Deaths of Statistics Norway.

Tissue Microarray (TMA)
The TMA technique has been described previously and validated in several studies.^41–45 Briefly, the area of highest tumor grade was identified on hematoxylin and eosin slides, and three tissue cylinders (0.6 mm) were punched from the selected area and mounted into the recipient paraffin block using a custom-made precision instrument (Beecher Instruments, Silver Spring, MD). In this study, TMA slides were used for P-cadherin and p120^ctn, whereas E-cadherin and ß-catenin were examined on standard slides.

Immunohistochemistry
E-cadherin and ß-catenin. Immunohistochemistry was performed on 5-µm-thick sections of formalin-fixed, paraffin-embedded tissues. For antigen retrieval, the sections were boiled for 10 minutes at 750 W and 15 minutes at 500 W in citrate buffer, in a microwave oven. The slides were incubated overnight at 4°C with the E-cadherin monoclonal antibody (clone HECD-1, catalog No. 13-1700, dilution 1:400; Zymed Laboratories, San Francisco, CA). For ß-catenin, the slides were incubated at room temperature for 25 minutes with the monoclonal antibody (clone 14, catalog No. 610154, dilution 1:800; BD Transduction Laboratories, Lexington, KY). The staining was performed on TechMate 500 automated slide processing equipment (DakoCytomation, Copenhagen, Denmark) using the standard avidin-biotin method. The peroxidase was localized by the diaminobenzidine tetrachloride peroxidase reaction with Harris hematoxylin as counterstain. Membranous staining in benign endometrial epithelium was used as positive internal control. Assessable staining was available in all 286 patient samples for ß-catenin and in 284 patient samples for E-cadherin.

p120^ctn and P-cadherin. A sufficient amount of tumor tissue was available in 276 patient samples using the tissue-conserving TMA technique. Immunohistochemical staining procedures were as described above. Antigen retrieval was performed by boiling for 10 minutes at 750 W and 15 minutes at 500 W in Target Retrieval Solution (TRS; DAKO) buffer, pH 6.0, in a microwave oven. An Autostainer (DAKO) was used for staining. The slides were incubated for 1 hour at room temperature with a monoclonal antibody for p120^ctn (clone 98, catalog no. 610134, dilution 1:3200; BD Transduction Laboratories) and with a monoclonal antibody for P-cadherin (clone 56, catalog No. 610228, dilution 1:100; BD Transduction Laboratories) for 1 hour at room temperature. Immunoperoxidase staining was carried out using the Envision Kit (DAKO) with diaminobenzidine tetrachloride peroxidase as substrate before counterstaining with Mayer's hematoxylin. In every run, control slides with benign endometrial epithelium and endometrial carcinoma tissue were included for comparison.

Evaluation of Staining Results
Staining was recorded by a semiquantitative and subjective grading system, considering the intensity of staining and the proportion of tumor cells showing a positive membranous reaction. Regarding the TMA slides, all three cores from each patient case were evaluated. Intensity was recorded as 0 (no staining) to 3 (strong staining); the percentage of membranous staining area was recorded as 0 (no positive tumor cells), 1 (< 10% positive tumor cells), 2 (10% to 50% positive tumor cells), and 3 (> 50% positive tumor cells). A staining index (SI) was calculated as the product of staining intensity and area. In general, the membrane staining of E-cadherin and ß-catenin was often found to be heterogenous. Cytoplasmic staining was often seen in addition to membranous staining for all markers, whereas nuclear staining was recorded separately for ß-catenin.

Immunohistochemical registration was performed blinded to patient characteristics and outcome for all four markers.

For internal validation, 20 regular slides were randomly selected and stained for both P-cadherin and p120^ctn. SIs for TMA sections were then compared with the regular slides, with 90% correspondence in SI for both markers (P < .0001 by ² test; = 0.78 and 0.79 for P-cadherin and p120^ctn, respectively).

In subsequent statistical analyses, cutoff points for SI categories mainly were based on median or quartile values, considering also the frequency distribution for each marker. Categories with similar survival estimates were merged. E-cadherin and ß-catenin SIs were categorized by median values; E-cadherin SI was categorized as high (> 3) or low (0 to 3), whereas ß-catenin SI was categorized as high (> 2) or low (0 to 2). For P-cadherin, tumors were classified by the upper quartile as high expressing (SI 6) or low expressing (SI < 6). Regarding p120^ctn, samples were classified by the lower quartile as low expressing (SI < 3) or high expressing (SI 3). Additional survival analyses, using individual SI levels, confirmed these categories.

Statistical Methods
Comparisons of groups were performed by Pearson ² or Mann-Whitney tests. Univariate survival analyses (using death as a result of endometrial carcinoma as end point; death from other causes were censored) were performed using the product-limit procedure (Kaplan-Meier method), with the time of primary operation as the entry date. The log-rank (Cox-Mantel) test was used to compare survival curves for different categories of each variable. Variables with impact on survival in univariate analyses (P .15) were examined by log-log plot to determine how these variables could be incorporated in Cox proportional hazards regression models. Tests for interactions were carried out for the variables that were significantly related to survival in Cox regression analysis. Data were analyzed using the SPSS software package (SPSS Inc, Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
E-Cadherin Expression
Reduced or low membranous expression of E-cadherin (n = 159; 56%) was significantly associated with the serous or papillary type (P = .002), high FIGO grade (P = .04), vascular invasion (P = .04), deep myometrial invasion ( 50%; P = .02), and high FIGO stage (P = .01), as listed in Table 1. Low E-cadherin expression was also associated with high nuclear grade (P = .002), solid growth more than 50% (P = .01), diffusely infiltrative growth pattern (P = .01), and high mitotic count (P = .03, Mann-Whitney test; data not shown).

View larger version (122K): [in this window] [in a new window]   Fig 1. Immunohistochemical staining showing (A) low and (B) high membranous expression of E-cadherin, (C) low and (D) high expression of beta-catenin, (E) high and (F) low expression of P-cadherin, and (G) low and (H) high expression of p120ctn.

P-Cadherin Expression
Eighty-three patient samples (30%) showed high membranous expression of P-cadherin, with a significantly higher proportion among the clear-cell or serous papillary type (P = .004). High expression also was associated with high FIGO grade (P < .001), vascular invasion (P = .01), deep myometrial infiltration (P < .001), and increasing FIGO stage (P = .02), as listed in Table 2. Strong P-cadherin expression also was significantly associated with high nuclear grade (P <. 001), solid growth (P = .03), and high mitotic count (P = .01, Mann-Whitney test; data not shown). Among the endometrioid tumors, high P-cadherin expression was significantly associated with high FIGO grade (P = .004), high nuclear grade (P < .001), and deep myometrial infiltration (P = .002).

Thirty-eight patient samples (15%) of the endometrioid subgroup showed this low expression of E-cadherin and high expression of P-cadherin, with a significant association to high mitotic count (P = .02, Mann-Whitney test) and deep myometrial infiltration (P = .002).

p120^ctn Expression
Reduced or low membrane expression of p120^ctn showed a significant association with increasing FIGO grade (P = .01; Table 2), and also was correlated with high mitotic count (P = .009, Mann-Whitney test), presence of necrosis (P = .04), and solid growth more than 50% (P = .004).

Associations Among Cell Adhesion Markers
Low expression of E-cadherin was significantly associated with low ß-catenin expression (P = .02; Spearman correlation coefficient, 0.13), whereas there were no other significant correlations among E-cadherin and the other adhesion markers. ß-catenin was significantly correlated only to p120^ctn (P = .006; Spearman correlation coefficient, 0.16). P-cadherin was not correlated to any markers in this study.

Associations With Other Biomarkers
Data on selected biomarkers were included from previous studies for comparisons.^46,47 Briefly, low E-cadherin expression was associated with increased mean microvessel density (P = .05). Low-grade expression of ß-catenin or p120^ctn was associated with loss of nuclear p16 expression (P = . 001 and P < . 001, respectively), and reduced ß-catenin staining was associated with increased tumor cell proliferation estimated by Ki-67 staining (P = .02, Mann-Whitney test). High P-cadherin expression showed a significant association with increased p53 protein expression (P = .01), also for the endometrioid subgroup (P =. 02). Tumors with low expression of E-cadherin and high expression of P-cadherin were significantly associated with tumor cell proliferation estimated by Ki-67 (P = .04, Mann-Whitney test).

Univariate Survival Analysis
All cellular adhesion markers were significantly associated with patient survival (Table 3; Fig 2). Combined reduction of E-cadherin and ß-catenin, which was present in 94 patients (33%), had an even stronger prognostic impact, with 62% estimated 5-year survival, compared with 89% and 78% estimated 5-year survival in tumors with no reduction or reduction of only one of the markers (intermediate expression), respectively (P = .0006).

View larger version (28K): [in this window] [in a new window]   Fig 2. Estimated survival among patients with endometrial carcinoma according to expression of (A) E-cadherin, (B) P-cadherin, (C) beta-catenin, and (D) p120ctn (Kaplan-Meier method).

View larger version (24K): [in this window] [in a new window]   Fig 3. Estimated survival among patients according to combined expression of (A) beta-catenin (ß-catenin) and P-cadherin, and (B) E-cadherin and P-cadherin (Kaplan-Meier method; results are missing in one patient for combined E-cadherin and P-cadherin expression).

Low-grade expression of p120^ctn (SI < 3) was associated with significantly decreased survival. Even more pronounced differences were obtained by comparing tumors with total loss (SI = 0) to the positive tumors, with an estimated survival of 47% v 78%, respectively (P = .0008), but because few tumors presented with complete loss (n = 19), the lower quartile was used as cut point.

All investigated variables influenced survival significantly in separate univariate analyses for the subgroup of endometrioid tumors, except for E-cadherin expression, which lost its survival influence (data not shown).

Multivariate Survival Analysis
Initially, each of the cell adhesion markers was studied in separate, parallel Cox models, together with basic tumor features such as histologic type, FIGO grade, vascular invasion, and myometrial infiltration. E-cadherin expression showed no independent prognostic impact in its model, whereas reduced ß-catenin expression, high P-cadherin expression, and low expression of p120^ctn all had an independent prognostic influence together with histologic type, FIGO grade, vascular invasion, and myometrial invasion.

We next examined all adhesion markers in a simultaneous model, in addition to the same basic variables (Table 4). Only patients with complete information on all variables were included (n = 247). As presented in Table 4, expression of ß-catenin, P-cadherin, and p120^ctn all had independent prognostic impact in addition to histologic type, FIGO grade, vascular invasion, and myometrial infiltration, whereas E-cadherin failed to obtain independent prognostic impact in this Cox model.

In subset analyses of the endometrioid subgroup, including all four adhesion markers together with FIGO grade, vascular invasion, and myometrial infiltration, P-cadherin had an independent prognostic significance (HR, 2.4; P = .007), together with ß-catenin (HR, 2.1; P = .05), p120^ctn (HR, 2.7; P = .003), FIGO grade (HR, 2.2; P = .01), vascular invasion (HR, 4.3; P = .001), and myometrial infiltration (HR, 2.3; P = .04), whereas E-cadherin had no independent prognostic significance (HR, 1.2; P = .4).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
In this study, increased membranous expression of P-cadherin was related to a subgroup of more aggressive endometrial cancers. This phenotype was significantly associated with adverse prognostic factors, including a higher mitotic rate, vascular invasion, deep myometrial infiltration, and reduced survival as confirmed by multivariate analysis. To our knowledge, the prognostic impact of this feature has not been studied previously in endometrial carcinoma, and our findings suggest that P-cadherin might be a novel marker in these tumors, similar to results found for breast cancer.^33,34

P-cadherin expression showed an independent prognostic significance in multivariate analysis, in addition to established and strong prognostic variables such as histologic type, FIGO grade, and FIGO stage. In the subgroup of endometrioid carcinomas, strong staining of P-cadherin was associated with high nuclear and histologic grade, deep myometrial infiltration, and pathologic expression of p53 protein, and still had an independent prognostic impact in multivariate analysis. These findings indicate that P-cadherin upregulation is important across the distinction between endometrioid and nonendometrioid tumors.

Downregulation of E-cadherin expression with concomitant upregulation of N-cadherin or P-cadherin, termed cadherin switching, has been reported for carcinomas in the esophagus, prostate, cervix, and ovary, and has been associated with tumor progression and metastatic disease.^48–51 Our results support the hypothesis that a cadherin switch also could represent an important step in tumor progression⁵² for endometrial carcinoma. Tumors with a low expression of E-cadherin and high expression of P-cadherin phenotype had vascular and deep myometrial invasion significantly more often as well as higher tumor cell proliferation, with significantly reduced survival, possibly related to a more invasive phenotype. These results were confirmed when the endometrioid subgroup was analyzed separately.

Few studies have investigated the prognostic role of altered ß-catenin expression in endometrial carcinoma. In a small study (33 patients) by Kim et al,¹⁶ no prognostic impact was reported. However, our data showed a significant and independent association between reduced membranous ß-catenin expression and patient survival, indicating that this could be a useful prognostic marker in addition to standard variables. Studies on gastric⁵³ and lung cancer¹⁰ have reported similar findings. Recently, Patel et al⁵¹ reported that coregulation of P-cadherin and ß-catenin could represent a critical step in the progression of ovarian cancer. In line with this, our study showed that patients who had endometrial tumors with a combination of low ß-catenin and high P-cadherin expression had a significantly worse prognosis, compared with the remaining patients.

Previous studies have reported an association between nuclear expression of ß-catenin and mutations in the corresponding CTNNB1 gene,^20,54–56 with a reported mutation frequency of 14% to 44%, especially in low-grade, low-stage tumors of the endometrioid subtype.^19–21 Tumors lacking ß-catenin mutations might also express nuclear ß-catenin, indicating that other gene inactivating mechanisms contribute.⁵⁶ Interestingly, we found that nuclear expression was detected in the endometrioid subtype only, supporting previous findings for mutations. In contrast, reduced membranous ß-catenin expression had no association to histologic type. Regarding prognosis, nuclear ß-catenin-expression had no prognostic significance in this series. The role of different patterns of ß-catenin expression in histologic subtypes of endometrial carcinoma must be clarified further.

Decreased expression of E-cadherin in endometrial carcinomas has been related to dedifferentiation and deep myometrial invasion.^13,14,57 Our data are in line with these observations. Weak expression was associated with a diffusely infiltrative growth pattern, supporting a role for E-cadherin in tumor cell invasion of surrounding tissues,⁴ similar to results shown for poorly differentiated gastric adenocarcinomas⁹ and lobular carcinomas of the breast.⁸ Decreased expression was more frequent in the nonendometrioid subtype compared with endometrioid carcinomas.¹⁷ In our study, low expression of E-cadherin influenced survival significantly in univariate analysis, and a combined low expression of E-cadherin and ß-catenin obtained even better prognostic impact than evaluation of E-cadherin alone, in line with a previous study of breast carcinoma.⁵⁸

The role of altered p120^ctn expression is not clarified in several human tumors. In our study, membranous expression of p120^ctn was downregulated or absent in a subgroup of tumors. There was no correlation between the expression of p120^ctn and E-cadherin, indicating an independent function of these molecules, similar to results found for breast carcinoma.²⁵ Decreased or absent p120^ctn was associated with significant survival differences in both univariate and multivariate analysis.

Vascular invasion is a marker of aggressive tumors and is essential for the development of metastatic disease.⁵⁹ In our study, altered expression of E-cadherin, ß-catenin, and P-cadherin was significantly associated with vascular involvement, indicating a relationship between decreased cell adhesion and migration of tumor cells into the vascular system. Whether this process depends on active tumor-associated angiogenesis should be studied further. A correlation between reduced E-cadherin expression and increased vascular invasion has been reported for gastric⁶⁰ and breast carcinomas.⁶¹ Compared with E-cadherin, we found an even stronger relationship between decreased ß-catenin expression and vascular invasion, similar to previously published results of a lung carcinoma study.¹⁰

Our study demonstrates a highly significant relationship between immunohistochemical staining by using the TMA technique compared with regular slides, in line with previous findings.⁶² This method represents a tissue-conserving and efficient way to examine multiple interesting and potentially important markers within various pathways or protein families. Care should be used, however, in the interpretation of selected tumor areas, and the results need to be validated in future studies.

In conclusion, our study indicates that altered expression of cell adhesion markers, among them P-cadherin and ß-catenin, is an important and frequent feature of endometrial cancer. P-cadherin expression also independently predicts decreased patient survival among the endometrioid tumors. Strong P-cadherin staining may serve as a useful and novel marker of endometrial cancer progression, possibly by indicating a more invasive phenotype. Our data also demonstrate that a shift from E-cadherin to P-cadherin expression (cadherin switch) is an important prognostic feature in these tumors.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Gerd Lillian Hallseth, Bendik Nordanger, and Randi Nygaard for excellent technical assistance.

	NOTES

 
Supported by the Research Council of Norway (grant No.143049/320), the Norwegian Cancer Society (grant No. 94070/001), Meltzer Research Foundation, and Helse Vest.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Abeler VM, Kjorstad KE: Endometrial adenocarcinoma in Norway: A study of a total population. Cancer 67:3093–3103, 1991[CrossRef][Medline]

2. Homesley HD, Zaino R: Endometrial cancer: Prognostic factors. Semin Oncol 21:71–78, 1994[Medline]

3. Zaino RJ, Kurman RJ, Diana KL, et al: Pathologic models to predict outcome for women with endometrial adenocarcinoma: The importance of the distinction between surgical stage and clinical stage—A Gynecologic Oncology Group study. Cancer 77:1115–1121, 1996[CrossRef][Medline]

4. Wijnhoven BP, Dinjens WN, Pignatelli M: E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg 87:992–1005, 2000[CrossRef][Medline]

5. Jiang WG: E-cadherin and its associated protein catenins, cancer invasion and metastasis. Br J Surg 83:437–446, 1996[Medline]

6. Takeichi M: Cadherins in cancer: Implications for invasion and metastasis. Curr Opin Cell Biol 5:806–811, 1993[CrossRef][Medline]

7. De Leeuw WJ, Berx G, Vos CB, et al: Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. J Pathol 183:404–411, 1997[CrossRef][Medline]

8. Siitonen SM, Kononen JT, Helin HJ, et al: Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol 105:394–402, 1996[Medline]

9. Gabbert HE, Mueller W, Schneiders A, et al: Prognostic value of E-cadherin expression in 413 gastric carcinomas. Int J Cancer 69:184–189, 1996[CrossRef][Medline]

10. Bremnes RM, Veve R, Gabrielson E, et al: High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non–small-cell lung cancer. J Clin Oncol 20:2417–2428, 2002[Abstract/Free Full Text]

11. Kanazawa T, Watanabe T, Kazama S, et al: Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region. Int J Cancer 102:225–229, 2002[CrossRef][Medline]

12. Cheng L, Nagabhushan M, Pretlow TP, et al: Expression of E-cadherin in primary and metastatic prostate cancer. Am J Pathol 148:1375–1380, 1996[Abstract]

13. Sakuragi N, Nishiya M, Ikeda K, et al: Decreased E-cadherin expression in endometrial carcinoma is associated with tumor dedifferentiation and deep myometrial invasion. Gynecol Oncol 53:183–189, 1994[CrossRef][Medline]

14. Leblanc M, Poncelet C, Soriano D, et al: Alteration of CD44 and cadherins expression: Possible association with augmented aggressiveness and invasiveness of endometrial carcinoma. Virchows Arch 438:78–85, 2001[CrossRef][Medline]

15. Schlosshauer PW, Ellenson LH, Soslow RA: Beta-catenin and E-cadherin expression patterns in high-grade endometrial carcinoma are associated with histological subtype. Mod Pathol 15:1032–1037, 2002[CrossRef][Medline]

16. Kim YT, Choi EK, Kim JW, et al: Expression of E-cadherin and alpha-, beta-, gamma-catenin proteins in endometrial carcinoma. Yonsei Med J 43:701–711, 2002[Medline]

17. Holcomb K, Delatorre R, Pedemonte B, et al: E-cadherin expression in endometrioid, papillary serous, and clear cell carcinoma of the endometrium. Obstet Gynecol 100:1290–1295, 2002[Abstract/Free Full Text]

18. Gumbiner BM: Signal transduction of beta-catenin. Curr Opin Cell Biol 7:634–640, 1995[CrossRef][Medline]

19. Palacios J, Catasus L, Moreno-Bueno G, et al: Beta- and gamma-catenin expression in endometrial carcinoma: Relationship with clinicopathological features and microsatellite instability. Virchows Arch 438:464–469, 2001[CrossRef][Medline]

20. Fukuchi T, Sakamoto M, Tsuda H, et al: Beta-catenin mutation in carcinoma of the uterine endometrium. Cancer Res 58:3526–3528, 1998[Abstract/Free Full Text]

21. Kobayashi K, Sagae S, Nishioka Y, et al: Mutations of the beta-catenin gene in endometrial carcinomas. Jpn J Cancer Res 90:55–59, 1999[CrossRef][Medline]

22. Anastasiadis PZ, Reynolds AB: The p120 catenin family: Complex roles in adhesion, signaling and cancer. J Cell Sci 113:1319–1334, 2000[Abstract]

23. Karayiannakis AJ, Syrigos KN, Alexiou D, et al: Expression patterns of the novel catenin p120cas in gastrointestinal cancers. Anticancer Res 19:4401–4405, 1999[Medline]

24. Nakopoulou L, Gakiopoulou-Givalou H, Karayiannakis AJ, et al: Abnormal alpha-catenin expression in invasive breast cancer correlates with poor patient survival. Histopathology 40:536–546, 2002[Medline]

25. Dillon DA, D'Aquila T, Reynolds AB, et al: The expression of p120ctn protein in breast cancer is independent of alpha- and beta-catenin and E-cadherin. Am J Pathol 152:75–82, 1998[Abstract]

26. Kallakury BV, Sheehan CE, Winn-Deen E, et al: Decreased expression of catenins (alpha and beta), p120 CTN, and E-cadherin cell adhesion proteins and E-cadherin gene promoter methylation in prostatic adenocarcinomas. Cancer 92:2786–2795, 2001[CrossRef][Medline]

27. Gold JS, Reynolds AB, Rimm DL: Loss of p120ctn in human colorectal cancer predicts metastasis and poor survival. Cancer Lett 132:193–201, 1998[CrossRef][Medline]

28. Shimazui T, Schalken JA, Giroldi LA, et al: Prognostic value of cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120cas) in bladder tumors. Cancer Res 56:4154–4158, 1996[Abstract/Free Full Text]

29. Syrigos KN, Karayiannakis A, Syrigou EI, et al: Abnormal expression of p120 correlates with poor survival in patients with bladder cancer. Eur J Cancer 34:2037–2040, 1998

30. Miyamoto S, Baba H, Kuroda S, et al: Changes in E-cadherin associated with cytoplasmic molecules in well and poorly differentiated endometrial cancer. Br J Cancer 83:1168–1175, 2000[CrossRef][Medline]

31. Moreno-Bueno G, Hardisson D, Sarrio D, et al: Abnormalities of E- and P-cadherin and catenin (beta-, gamma-catenin, and p120ctn) expression in endometrial cancer and endometrial atypical hyperplasia. J Pathol 199:471–478, 2003[CrossRef][Medline]

32. Shimoyama Y, Hirohashi S, Hirano S, et al: Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas. Cancer Res 49:2128–2133, 1989[Abstract/Free Full Text]

33. Peralta Soler A, Knudsen KA, Salazar H, et al: P-cadherin expression in breast carcinoma indicates poor survival. Cancer 86:1263–1272, 1999[CrossRef][Medline]

34. Gamallo C, Moreno-Bueno G, Sarrio D, et al: The prognostic significance of P-cadherin in infiltrating ductal breast carcinoma. Mod Pathol 14:650–654, 2001[CrossRef][Medline]

35. van der Linden PJ, de Goeij AF, Dunselman GA, et al: P-cadherin expression in human endometrium and endometriosis. Gynecol Obstet Invest 38:183–185, 1994[Medline]

36. Cancer in Norway 1996. The Cancer Registry of Norway, Oslo, Institute for Epidemiological Cancer Research, 1999

37. Mikuta JJ: International Federation of Gynecology and Obstetrics staging of endometrial cancer 1988. Cancer 71:1460–1463, 1993[Medline]

38. Announcements: FIGO stages—1988 Revision. Gynecol Oncol 35:125–127, 1989[CrossRef]

39. Zaino RJ, Kurman RJ, Diana KL, et al: The utility of the revised International Federation of Gynecology and Obstetrics histologic grading of endometrial adenocarcinoma using a defined nuclear grading system: A Gynecologic Oncology Group study. Cancer 75:81–86, 1995[CrossRef][Medline]

40. Lax SF, Kurman RJ, Pizer ES, et al: A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis. Am J Surg Pathol 24:1201–1208, 2000[Medline]

41. Kononen J, Bubendorf L, Kallioniemi A, et al: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847, 1998[CrossRef][Medline]

42. Hoos A, Urist MJ, Stojadinovic A, et al: Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors. Am J Pathol 158:1245–1251, 2001[Abstract/Free Full Text]

43. Nocito A, Bubendorf L, Maria Tinner E, et al: Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade. J Pathol 194:349–357, 2001[CrossRef][Medline]

44. Straume O, Akslen LA: Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and ephrin-A1/EphA2 on melanoma progression. Am J Pathol 160:1009–1019, 2002[Abstract/Free Full Text]

45. Halvorsen OJ, Haukaas SA, Akslen LA: Combined loss of PTEN and p27 expression is associated with tumor cell proliferation by Ki-67 and increased risk of recurrent disease in localized prostate cancer. Clin Cancer Res 9:1474–1479, 2003[Abstract/Free Full Text]

46. Salvesen HB, Das S, Akslen LA: Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis. Clin Cancer Res 6:153–159, 2000[Abstract/Free Full Text]

47. Salvesen HB, Iversen OE, Akslen LA: Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: A population-based endometrial carcinoma study. J Clin Oncol 17:1382–1390, 1999[Abstract/Free Full Text]

48. Bailey T, Biddlestone L, Shepherd N, et al: Altered cadherin and catenin complexes in the Barrett's esophagus-dysplasia-adenocarcinoma sequence: Correlation with disease progression and dedifferentiation. Am J Pathol 152:135–144, 1998[Abstract]

49. Tomita K, van Bokhoven A, van Leenders GJ, et al: Cadherin switching in human prostate cancer progression. Cancer Res 60:3650–3654, 2000[Abstract/Free Full Text]

50. de Boer CJ, van Dorst E, van Krieken H, et al: Changing roles of cadherins and catenins during progression of squamous intraepithelial lesions in the uterine cervix. Am J Pathol 155:505–515, 1999[Abstract/Free Full Text]

51. Patel IS, Madan P, Getsios S, et al: Cadherin switching in ovarian cancer progression. Int J Cancer 106:172–177, 2003[CrossRef][Medline]

52. Hajra KM, Fearon ER: Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer 34:255–268, 2002[CrossRef][Medline]

53. Utsunomiya T, Doki Y, Takemoto H, et al: Clinical significance of disordered beta-catenin expression pattern in human gastric cancers. Gastric Cancer 3:193–201, 2000[Medline]

54. Machin P, Catasus L, Pons C, et al: CTNNB1 mutations and beta-catenin expression in endometrial carcinomas. Hum Pathol 33:206–212, 2002[CrossRef][Medline]

55. Moreno-Bueno G, Gamallo C, Perez-Gallego L, et al: Beta-catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. Diagn Mol Pathol 10:116–122, 2001[CrossRef][Medline]

56. Moreno-Bueno G, Hardisson D, Sanchez C, et al: Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene 21:7981–7990, 2002[CrossRef][Medline]

57. Saito T, Nishimura M, Yamasaki H, et al: Hypermethylation in promoter region of E-cadherin gene is associated with tumor dedifferentiation and myometrial invasion in endometrial carcinoma. Cancer 97:1002–1009, 2003[CrossRef][Medline]

58. Bukholm IK, Nesland JM, Kåresen R, et al: E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. J Pathol 185:262–266, 1998[CrossRef][Medline]

59. Liotta LA, Kohn E: Cancer invasion and metastases. JAMA 263:1123–1126, 1990[CrossRef][Medline]

60. Tanaka M, Kitajima Y, Edakuni G, et al: Abnormal expression of E-cadherin and beta-catenin may be a molecular marker of submucosal invasion and lymph node metastasis in early gastric cancer. Br J Surg 89:236–244, 2002[Medline]

61. Gupta A, Deshpande CG, Badve S: Role of E-cadherins in development of lymphatic tumor emboli. Cancer 97:2341–2347, 2003[CrossRef][Medline]

62. Gillett CE, Springall RJ, Barnes DM, et al: Multiple tissue core arrays in histopathology research: A validation study. J Pathol 192:549–553, 2000[CrossRef][Medline]

Submitted September 9, 2003; accepted January 19, 2004.

This article has been cited by other articles:

				M. J. Wheelock, Y. Shintani, M. Maeda, Y. Fukumoto, and K. R. Johnson Cadherin switching J. Cell Sci., March 15, 2008; 121(6): 727 - 735. [Abstract] [Full Text] [PDF]

				K. Gravdal, O. J. Halvorsen, S. A. Haukaas, and L. A. Akslen A Switch from E-Cadherin to N-Cadherin Expression Indicates Epithelial to Mesenchymal Transition and Is of Strong and Independent Importance for the Progress of Prostate Cancer Clin. Cancer Res., December 1, 2007; 13(23): 7003 - 7011. [Abstract] [Full Text] [PDF]

				I. M. Stefansson, H. B. Salvesen, and L. A. Akslen Vascular proliferation is important for clinical progress of endometrial cancer. Cancer Res., March 15, 2006; 66(6): 3303 - 3309. [Abstract] [Full Text] [PDF]

				K. Collett, G. E. Eide, J. Arnes, I. M. Stefansson, J. Eide, A. Braaten, T. Aas, A. P. Otte, and L. A. Akslen Expression of Enhancer of Zeste Homologue 2 Is Significantly Associated with Increased Tumor Cell Proliferation and Is a Marker of Aggressive Breast Cancer Clin. Cancer Res., February 15, 2006; 12(4): 1168 - 1174. [Abstract] [Full Text] [PDF]

				I. M. Bachmann, O. J. Halvorsen, K. Collett, I. M. Stefansson, O. Straume, S. A. Haukaas, H. B. Salvesen, A. P. Otte, and L. A. Akslen EZH2 Expression Is Associated With High Proliferation Rate and Aggressive Tumor Subgroups in Cutaneous Melanoma and Cancers of the Endometrium, Prostate, and Breast J. Clin. Oncol., January 10, 2006; 24(2): 268 - 273. [Abstract] [Full Text] [PDF]

				I. M. Bachmann, O. Straume, H. E. Puntervoll, M. B. Kalvenes, and L. A. Akslen Importance of P-Cadherin, {beta}-Catenin, and Wnt5a/Frizzled for Progression of Melanocytic Tumors and Prognosis in Cutaneous Melanoma Clin. Cancer Res., December 15, 2005; 11(24): 8606 - 8614. [Abstract] [Full Text] [PDF]

				K. Collett, I. M. Stefansson, J. Eide, A. Braaten, H. Wang, G. E. Eide, S. O. Thoresen, W. D. Foulkes, and L. A. Akslen A Basal Epithelial Phenotype Is More Frequent in Interval Breast Cancers Compared with Screen Detected Tumors Cancer Epidemiol. Biomarkers Prev., May 1, 2005; 14(5): 1108 - 1112. [Abstract] [Full Text] [PDF]

				K. Taniuchi, H. Nakagawa, M. Hosokawa, T. Nakamura, H. Eguchi, H. Ohigashi, O. Ishikawa, T. Katagiri, and Y. Nakamura Overexpressed P-Cadherin/CDH3 Promotes Motility of Pancreatic Cancer Cells by Interacting with p120ctn and Activating Rho-Family GTPases Cancer Res., April 15, 2005; 65(8): 3092 - 3099. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles