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Regular Articles |
From Departamento de Anatomía
Patológica*
and Departamento de
Ginecología y Obstetricia,
Hospital La
Paz, Madrid, Spain
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Relatively little is known about the molecular events that lead to the development of ovarian cancer, and no molecular markers are generally accepted as prognostic indicators. Although most cases of epithelial tumors of the ovary seem to have a common origin in the surface epithelium covering the ovary, different pathways and genetic alterations have been implicated in the development of cystadenomas, borderline tumors, and carcinomas of different histological subtypes and stages of progression. For example, loss of heterozygocity and a complete loss of chromosome 17 is characteristic of the advanced stages of serous carcinomas,5 whereas ras mutation participates in the development of tumors with mucinous differentiation, but not in other histological types.6 Recently, we have reported data that strongly suggest that ß-catenin may function as an oncogen in the initiation of some ovarian endometrioid carcinomas in which ß-catenin is mainly expressed in the nucleus and cytoplasm.7 However, the clinical implications of this finding remain to be established.
ß-Catenin is a multifunctional protein involved in at least two
important biological processes: cell-cell adhesion and signal
transduction (transcriptional activation).8
The role of
ß-catenin in adhesion is well established. In the adherens junctions
of epithelial cells, the cytoplasmic domain of E-cadherin organizes a
peripheral protein complex, including 
-catenin, ß-catenin, and
-catenin (plakoglobin), that is necessary for adhesion to
occur.9
The role of ß-catenin in the linkage between
-catenin and E-cadherin in this complex is probably regulated by
epidermal growth factor-mediated tyrosine phosphorylation of the
ß-catenin.8,9
Molecules of the cadherin/catenin complex
have been implicated in differentiation and tumor progression, because
their reduced expression is not only frequent in poorly differentiated
tumors, but also might produce loss of adhesiveness and increased
invasive and metastatic potential.10-13
In addition, ß-catenin participates in the transduction of signals and activates transcription by forming complexes with DNA binding proteins in the T-cell factor-lymphoid enhancer factor (TcF-lef) family.14 The free (cytoplasmic) ß-catenin level is low in normal cells because the protein is targeted for destruction in the ubiquitin-proteasome system15 by adenomatous polyposis coli (APC) protein together with glycogen synthetase kinase-3ß (GSK-3ß)16 and other molecules such as axin or conductin8 ; thus wild-type APC plays an essential role in the clearance of unnecessary ß-catenin from the cytoplasm. Disruption of the APC-mediated regulation of the ß-catenin-Tcf pathway was first implicated in the development of colon carcinomas and melanoma.17,18 Mutations that inactivate APC increase cytoplasmic levels of free ß-catenin,19 which may then act as an oncoprotein through constitutive ß-catenin-Tcf-regulated transcription.14 In the same manner, activating ß-catenin mutations render this pathway insensitive to the effect of WT APC.17,18 To date, oncogenic ß-catenin mutations have been described in several malignancies, such as carcinomas of the colon,17,20-23 ovary,7 prostate,24 liver,25 and endometrium26 and medulloblastomas.27
This study analyzes the expression pattern of ß-catenin in a series of 69 stage I and II ovarian carcinomas and their relationships with ß-catenin gene mutation, clinicopathological features, and survival to better understand the biological and clinical relevance of ß-catenin pathway activation in ovarian cancer. Some of the clinicopathological and genetic features of 30 cases have previously been reported.7
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study was conducted on 69 primary ovarian carcinomas diagnosed at the Department of Pathology of La Paz Hospital, Madrid. All cases were in stage I or II and had a minimum follow-up period of 5 years. Staging was done following the International Federation of Gynecology and Obstetrics (FIGO) system. Retrospective reviews of patient files were performed to obtain all pertinent data on the primary tumor, type of surgery, adjuvant treatment, recurrence, and survival. If necessary, patients were retrospectively assigned a FIGO stage on the basis of their clinical history. The tumors were routinely fixed in 10% formalin and embedded in paraffin. Histological typing was performed according to the World Health Organization classification. Histological, immunohistochemical, and DNA studies were performed on formalin-fixed, paraffin-embedded tissue samples.
Immunohistochemistry
Immunohistochemistry for ß-catenin was performed by the avidin-biotin-alkaline phosphatase method, as previously reported.7 A heat-induced antigen retrieval step (deparaffinized sections were immersed in 0.01 mol/L sodium citrate buffer (pH 6.0) and incubated in a pressure cooker for 3 minutes) was performed. The mouse anti-human ß-catenin monoclonal antibody (Transduction Laboratories, Lexington, KY) was applied at a dilution of 1:200. In negative controls, the primary antibody was omitted or replaced with an irrelevant antibody.
Evaluation of Immunohistochemical Staining
Two patterns of ß-catenin expression were considered: membranous, if ß-catenin was localized in the cell membrane only; and nuclear, when ß-catenin was expressed in the nucleus, irrespective of the percentage of stained nuclei or simultaneous expression of ß-catenin in membrane and cytoplasm.
A semiquantitative estimation of membranous ß-catenin expression was made, using a composite score obtained by adding the values of the immunoreaction intensity and relative abundance of the ß-catenin immunoreactive cells, as previously reported for cadherins.28,29 Briefly, the intensity was graded from 0 (equivalent to background staining of the acellular stroma) to +3 (intense stain equivalent to normal surface epithelium). The abundance of ß-catenin-positive cells was graded from 0 to 4 (0 = less than 5% of positive cells; 1 = 5–25%; 2 = 26–50%; 3 = 51–75%; 4 = 76–100%). ß-Catenin expression was considered preserved when the composite score was 6 or 7. Cases with scores between 0 and 5 were considered to be tumors with reduced ß-catenin expression.
DNA Analysis
Polymerase chain reaction (PCR) was performed as previously reported7 on 25 tumors and corresponding normal tissue: all 13 endometrioid tumors as well as 12 carcinomas of other histological types (four serous, two clear cell, two mucinous, and two mixed). DNA was extracted from paraffin blocks containing a large proportion of epithelial tumor cells (>75%), but no microdissection of selected areas was performed. Normal tissue in each case consisted of samples from fallopian tube or myometrium.
The primers used were 240F (ATG GAA CCA GAC AGA AAA GC) and 439F (GCT ACT TGT TCT GAG TGA AG), which amplified a 200-bp fragment of exon 3 of the ß-catenin gene, encompassing the sequence for GSK-3ß phosphorylation. After purification, PCR products were sequenced in a 373 Automated Sequencer or a 310 Automater Sequencer (Applied Biosystems, Foster City, CA), using the Abi Prism dRodhamine Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems). PCR primers were used as the primers for sequencing the two strands of the amplified products. Cases with abnomal DNA sequences were subjected to DNA extraction from additional tissue sections, PCR, and sequencing, to confirm the presence of true mutations.
Statistical Methods
The 
2
test was used to analyze the statistical
significance of the relationship between ß-catenin expression and the
clinicopathological and immunohistochemical variables. Relapse-free
survival and overall survival, defined as the time from diagnosis to
relapse or death, respectively, were used as a measure of prognosis.
Univariate survival curves were estimated using the Kaplan and Meier
method and compared using the log rank test. Multivariate analysis was
done using Cox's proportional hazards regression model. Analyses were
carried out using JMP (Version 3.0.1; SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Some clinicopathological, inmunohistochemical, and genetic features of 30 cases have previously been reported.7 The mean age of the 69 patients was 55 years (range 19–77). There were 19 (27.5%) stage Ia, 4 (6%) stage Ib, 28 (40.5%) stage Ic, 5 (7%) stage IIa, 9 (13%) stage IIb, and 4 (6%) stage IIc tumors. There were 27 (39%) grade I carcinomas, 28 (41%) grade II, and 14 (20%) grade III. No patient showed macroscopic residual disease after surgery. All patients received postoperative therapy: 17 (24.6%) radiotherapy and 52 (75.4%) chemotherapy: 33 melphalan and adryamicine, 15 melphalan alone, and 4 cisplatin-based chemotherapy.
ß-Catenin Expression and Correlations with Clinicopathological Features
All analyzed tumors showed membrane ß-catenin expression with
variable extension and intensity, but simultaneous nuclear ß-catenin
expression (nuclear pattern) was observed in only 11 (16%) ovarian
carcinomas (Figure 1A)
; the remaining 58
tumors (84%) only had membrane expression (membranous pattern) (Figure 1B)
. The expression pattern (nuclear versus membranous)
correlated significantly with the histological type (Table 1)
, inasmuch as 9 cases with nuclear
expression were endometrioid carcinomas. Nuclear expression was also
observed in two serous carcinomas. In endometrioid lesions, the
percentage of stained nuclei ranged between 25% and 90% of the
neoplastic cells. In contrast, in serous carcinomas the percentage of
immunoreactive nuclei did not exceed 5%. The different ß-catenin
expression patterns did not correlate with tumor grade and stage. In
addition, postoperative therapy was similar in tumors with a nuclear or
membranous ß-catenin expression pattern (Table 1)
.
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. Endometrioid carcinomas with
ß-catenin membranous expression only did not have squamous
metaplasia, and two cases had a growth pattern resembling that of
sex-cord stromal tumors. Four mixed carcinomas with an endometrioid
component showed only ß-catenin membranous expression. Nuclear
ß-catenin expression was observed in epithelial cells of
endometriotic cyst (Figure 1C)
adjacent to an endometrioid carcinoma
with ß-catenin nuclear expression.
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Direct sequence analysis of the PCR amplification products
showed heterozygous substitution mutations of ß-catenin gene exon 3
in seven endometrioid carcinomas with nuclear ß-catenin expression:
three at codon 32 (Figure 1E and 1F)
, one at codon 33 (Figure 1F)
, two
at codon 37, and one at codon 41. At codon 32, two GAC to TAC (D32Y)
changes and a GAC to GGC (D32G) change were observed; at codon
33, a TCT to TGT change (S33C) was observed; at codon 37, a TCT to TTT
change (S37F) and a TCT to TGT change (S37C) were observed; and
finally, an ACC to GCC change at codon 41 (T41A) was observed. To
further confirm sequencing data in the cases with mutation in S37, PCR
products were digested with XmnI restriction
endonuclease. Mutations affecting codons 32 and 33 were confirmed by
HinfI restriction analysis (Figure 1H)
. All detected
mutations were also confirmed by resequencing.
No ß-catenin gene mutations were observed in two endometrioid
carcinomas with nuclear ß-catenin expression pattern, four
endometrioid carcinomas with a membranous ß-catenin pattern (Table 3)
, or 12 non-endomterioid carcinomas, two serous carcinomas with focal
nuclear ß-catenin expression, and 10 carcinomas with membranous
ß-catenin pattern.
Outcome Analysis
The mean follow-up time of the study was 8.9 ± 6.8 years (range 1–24 years; median follow-up period 7 years). Among the 69 patients, 19 (33.3%) showed a relapse, which occurred between 4 and 46 months after surgery. All patients who relapsed subsequently died (13–48 months after surgery) of the disease.
The variables analyzed were the type of postoperative therapy (radiotherapy, melphalan, melphalan and adryamicine, and cisplatinun- based chemotherapy), histological type, histological grade, stage (Ia-b versus Ic-II), ß-catenin expression pattern (nuclear versus membranous), and membrane ß-catenin expression (preserved versus reduced).
Relapse-free survival was significantly related to histological grade
(2 = 26.61; P = 0.0000), stage
(2 = 9.61; P = 0.0019), and
ß-catenin expression pattern (2 = 5.82;
P = 0.016), but was unrelated to the type of
postoperative therapy (2 = 5.11; P
= 0.163), membrane ß-catenin expression (2 =
1.93; P = 0.164), and histological type
(2 = 6.88; P = 0.153) in the
univariate analysis. Multivariate analysis also selected
histological grade (2 = 16.82; P =
0.0022; risk ratio = 4.63; 95% confidence interval =
1.40–20.82), stage (2 = 7.96; P
= 0.0048; risk ratio = 5.81; 95% confidence interval =
1.61–37.18), and ß-catenin pattern (2 =
1028; P = 0.003; risk ratio = 0.000005) as
independent predictors of relapse-free survival.
Overall survival was also significantly related to histological grade
(2 = 21.12; P = 0.0000), stage
(2 = 9.92; P = 0.0016), and
ß-catenin expression pattern (2 = 6.74;
P = 0.0094), but was unrelated to the type of
postoperative therapy (2 = 3.39; P
= 0.334), membrane ß-catenin expression (2 =
1.38; P = 0.51), and histological type
(2 = 6.37; P = 0.17) in the
univariate analysis. Multivariate analysis also selected histological
grade (2 = 12.25; P = 0.0022; risk
ratio = 4.13; 95% confidence interval = 1.25–18.54), stage
(2 = 7.54; P = 0.0060; risk
ratio = 5.54; 95% confidence interval = 1.54–35.41), and
ß-catenin pattern (2 = 8.91; P =
0.0028; risk ratio = 0.000005), as independent predictors of OS.
The nuclear pattern of ß-catenin expression was an indicator of good
prognosis, inasmuch as not one recurrence or death occurred among these
patients.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ovarian carcinomas may arise de novo from surface ovarian epithelium (or epithelial inclusion cysts) or from benign or borderline lesions.30 It has been suggested that most serous carcinomas arise de novo, whereas most mucinous carcinomas originate from benign or borderline tumors.31 A proportion of endometrioid carcinomas may arise from previous benign lesions such as endometriosis and benign tumors of the same histological type.32,33 Endometrioid tumors of the ovary are either benign, usually taking the form of an adenofibroma or cystoadenofibroma, or overtly malignant. Between these two well-established categories, there is a spectrum of lesions that have received different names in the literature (proliferating endometrioid adenofibromas,32 atypical and borderline endometriod adenofibromas,33 proliferative endometrioid adenofibromas, and endometrioid tumors of low malignant potential34,35 ). Proliferating, borderline, or low-malignant-potential endometrioid tumors are characterized by adenocystadenofibromatous or papillary growth, epithelial proliferation, and atypia without stromal invasion.32-35 In addition, they frequently show squamous metaplasia and have an excellent prognosis, although carcinomas may arise in them.32-35 We previously reported ß-catenin mutation in one borderline or low-malignant-potential endometrioid tumor. In this study we observed ß-catenin nuclear expression in five carcinomas with large areas of endometrioid tumor of low malignant potential, four of which had ß-catenin mutations. Although we have not studied benign endometrioid adenofibromas, these data indicate that ß-catenin mutation would be implicated in the transformation process leading to the development of a subgroup of endometrioid carcinomas that have borderline or low-malignant-potential endometrioid tumors as their precursor. In addition, the observation of ß-catenin nuclear expression in endometriotic glands adjacent to one carcinoma with ß-catenin gene mutation suggests that ß-catenin could be implicated in the malignant transformation of some cases of endometriosis.
We also observed ß-catenin mutations in three endometrioid carcinomas without associated preinvasive areas but with evident squamous metaplasia. In contrast, none of the four endometrioid tumors with only membranous expression of ß-catenin and without ß-catenin mutations had squamous metaplasia. This finding may indicate that ß-catenin mutations could be implicated in the genesis of so-called adenoacanthomas, a suggestion that must be confirmed in a larger series of cases.
Since the original description of oncogenic ß-catenin mutation, several tumor types have been analyzed. ß-Catenin point mutations have been reported in 2%, 5%, 13%, and 19% of medulloblastomas,27 prostate carcinomas,24 endometrial carcinomas,26 and hepatocellular carcinomas,25 respectively. Candidus et al36 have not found evidence for mutation in this gene in gastric (diffuse and intestinal subtypes) and breast (ductal and lobular subtypes) carcinomas, although their sample was small. In ovarian carcinomas, we have observed ß-catenin mutations in only 10% of all stage I and II tumors analyzed, but in 50% of the endometrioid carcinomas. This is the highest frequency of ß-catenin mutation so far reported in any histological type of human carcinoma and is probably due to the characteristics of the sample analyzed (low stages and a high proportion of cases originated in preinvasive lesions).
Most studies on ß-catenin mutations have only studied the consensus sequence for GSK-3ß phosphorylation in exon 3. Mutations affecting this sequence, mainly in the amino acids implicated in the down-regulation of ß-catenin through phosphorylation by this serine/threonine kinase (Ser,33 Ser,37, Thr41, and Ser45),17 probably render a fraction of cellular ß-catenin insensitive to APC-mediated down-regulation and are responsible for the up-regulation of cytoplasmic ß-catenin and its distribution in the nuclei of tumor cells, as was immunohistochemically detected in the present series. Mutation at codon 32 changing a highly conserved aspartic acid was observed in three ovarian carcinomas. Mutations have been reported at this codon in hepatocellular25 and prostate25 carcinomas, and it has been suggested that the alteration may change the protein structure and inhibit phosphorylation.
Although all reported ß-catenin point mutations in human carcinoma
samples affect the sequence for GSK-3ß phosphorylation, the frequency
of mutations at each codon and the type of mutation differ by tumor
type, probably indicating different etiologies (Figure 2)
. For example, in hepatocellular
carcinoma, but not in other tumor types, the change from G to A or T
predominates.25
These types of ß-catenin mutations have
been reported in colon carcinomas induced by
azoxymethane37
and heterocyclic amines,38
which have a preference for forming DNA adducts at guanines. In
endometrial carcinoma, 50% of the mutations are C to T changes,
suggesting the action of carcinogens that induce deamination of DNA
bases.26
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It is also possible that the nucleocytoplasmic pattern of ß-catenin immunoexpression in the two cases without ß-catenin gene mutations was due to some alteration in other molecules of the ß-catenin-Tcf signaling pathway. At present, it appears that the intracellular pool of ß-catenin is regulated by an active GSK-3ß that recognizes an APC-ß-catenin complex.8 The role of APC in this complex is still poorly understood, but it has been suggested that APC may be involved in directing ß-catenin to proteasomes.15 APC contains ß-catenin binding and degradation sites, as well as binding sites for GSK-3ß. Thus the cytoplasmic ß-catenin pool can be increased in response not only to mutations in the ß-catenin gene, but also to extracellular Wg/Wnt signaling,39 which would inactivate GSK-3ß, or to genetic defects affecting GSK-3ß or APC. Expression of different Wnt factors has been described in human carcinomas,40,41 but to date their effect in ß-catenin levels has not been reported. In addition, the expression pattern for these factors in ovarian cancer remains to be established. The role of GSK-3ß in human oncogenesis is not well known. Recent studies do not report any alterations of GSK-3ß in medulloblastomas and colon carcinomas, some of which have mutations of the ß-catenin gene.23,27 Increased ß-catenin cytoplasmic and nuclear levels can also be observed in cases of APC inactivation (ie, mutations of APC in colorectal polyps and carcinomas19,42 and other conditions, such as sporadic aggressive fibromatosis43 ). Loss of heterozygosity has been reported at the APC locus in sporadic ovary carcinomas with a frequency of 50% in a series that included only four endometrioid carcinomas44 ; nevertheless, this seems to be a late event in tumor progression and does not correlate with mutation in the APC gene.44
We did not observe ß-catenin mutations in serous, mucinous clear cell, or mixed carcinomas, including four mixed tumors with an endometrioid component and two serous carcinomas with focal nuclear ß-catenin immunoexpression. In these two cases we did not perform microdissection of the nuclear immunostained areas, and we could not exclude mutations in these cases. ß-Catenin mutations have been reported as occurring focally in some prostate cancers, suggesting that these mutations may occur during tumor progression.24 Interestingly, two of the colon cancers reported by Kitaeva et al21 and two colon cancer cell lines (HCT 116 and SW48), which have ß-catenin gene mutations, also show a replication error-positive phenotype, suggesting that the activating mutations in ß-catenin that occur in some tumors may be associated with an underlying defect in DNA mismatch repair.
In the present series, the significant prognostic value of the traditional clinicopathological variables (grade and stage) as predictors of relapse-free and overall survival at 5 years in early-stage ovarian cancer2-4 was confirmed. In addition, the ß-catenin expression pattern was selected as an independent prognostic marker, indicating that cases with nuclear expression have an excellent prognosis, with no relapses or deaths among them. Obviously, these results must be taken as preliminary because of the small number of cases, but they do suggest ß-catenin as a potential prognostic marker that could be analyzed in larger series from different institutions. Although we did not observe any deaths among endometrioid carcinomas with a nuclear ß-catenin expression pattern, three of the four patients with endometrioid carcinomas with only membranous expression died. These findings suggest two oncogenic pathways in endometrioid carcinomas with different clinical implications. Identification of molecular defects in the subgroup of patients without nuclear ß-catenin expression and with apparently poor prognosis would be helpful in selecting a specific therapy for each patient.
In addition to the role of ß-catenin in signal transduction, this
molecule has a pivotal role in cell adhesion through its participation
in the cadherin/catenin complex of adherens junctions. Changes in the
expression and structure of ß-catenin lead to loss of adhesiveness
and may promote invasiveness and metastasis in tumor
cells.9,12,13
Mutations of ß-catenin disrupting the
interaction between E-cadherin and -catenin have been described in
tumor cell lines that grow as loose aggregates or single
cells.45,46
In human tumors, the expression of membranous
ß-catenin has been analyzed in head and neck,47
esophageal,48,49
gastric,50
colon,51
breast,52
and
ovarian53,54
carcinomas. It has been observed that 88% of
head and neck squamous cell carcinomas, 70% of esophageal carcinomas,
50% of gastric carcinomas, and 30% of infiltrating ductal carcinomas
of the breast show reduced membranous ß-catenin expression. In some
reports, reduced expression of ß-catenin has been correlated with
poorly differentiated tumors, advanced stage, and poor
survival.48,50
Davis et al54
observed reduced immunohistochemical
ß-catenin expression in 21% of a series of 34 ovarian carcinomas,
but Fujimoto et al53
did not find differences in mRNA
ß-catenin expression between normal ovary tissue and ovarian
carcinomas. We observed reduced membranous ß-catenin expression in
78% of our ovarian carcinomas. ß-Catenin expression did not
correlate with histological type, tumor differentiation, progression
(stage), or survival. However, it should be remembered that other
molecules of the cadherin/catenin complex may be more important than
ß-catenin in modulating adhesion in ovarian carcinomas. For example,
-catenin was reduced in approximately 60% of cases in a large
series of stage I and II ovarian carcinomas, and severe reduction of
-catenin expression (<30%) in stage I ovarian carcinomas was a
predictor of poor prognosis in the univariate and multivariate
analysis.55
In summary, the pattern of ß-catenin expression differs between ovarian carcinomas of differing histological types. APC-ß-catenin-Tcf signaling pathway activation secondary to oncogenic ß-catenin mutation is characteristic of a group of endometrioid carcinomas with nuclear ß-catenin expression and a good prognosis, most of which originate in previous benign or borderline lesions. Endometrioid carcinomas with only membrane expression of ß-catenin seem to represent a different subgroup of carcinomas that is not associated with the ß-catenin signaling pathway and which, probably, has a worse prognosis. Determination of the ß-catenin expression pattern in early-stage ovarian cancer might prove to be a useful marker for selecting low-risk patients.
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Acknowledgements |
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Footnotes |
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Supported by research grants 98/0151 from the Fondo de Investigaciones Sanitarias de la Seguridad Social, CAM 08.1/0020/1997 from the Comunidad Autónoma de Madrid, and SAF 98-0085-C03-03 from the Ministerio de Educación y Cultura, Spain.
Accepted for publication April 11, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and ß-catenin genes in human gastric and breast cancer. Cancer Res 1996, 56:49-36, ß, and -catenins and p120) in colorectal polyps. Am J Pathol 1997, 150:1977-1984[Abstract]
-catenin, ß-catenin and plakoglobin in esophageal carcinoma and its prognostic significance. Oncology 1997, 54:158-165[Medline]
-catenin. Histopathology 1996, 29:139-146[Medline]
- and ß-catenin mRNAs in ovarian cancers. Cancer Lett 1997, 115:207-212[Medline]
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-catenin, collagen IV, and Ki-67 expression in epithelial ovarian cancer. J Clin Oncol 1998, 16:2591-2600[Abstract]
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J. E. Pawlowski, J. R. Ertel, M. P. Allen, M. Xu, C. Butler, E. M. Wilson, and M. E. Wierman Liganded Androgen Receptor Interaction with beta -Catenin. NUCLEAR CO-LOCALIZATION AND MODULATION OF TRANSCRIPTIONAL ACTIVITY IN NEURONAL CELLS J. Biol. Chem., May 31, 2002; 277(23): 20702 - 20710. [Abstract] [Full Text] [PDF]
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Y. Zhai, R. Wu, D. R. Schwartz, D. Darrah, H. Reed, F. T. Kolligs, M. T. Nieman, E. R. Fearon, and K. R. Cho Role of {beta}-Catenin/T-Cell Factor-Regulated Genes in Ovarian Endometrioid Adenocarcinomas Am. J. Pathol., April 1, 2002; 160(4): 1229 - 1238. [Abstract] [Full Text] [PDF]
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R. Wu, Y. Zhai, E. R. Fearon, and K. R. Cho Diverse Mechanisms of {beta}-Catenin Deregulation in Ovarian Endometrioid Adenocarcinomas Cancer Res., November 1, 2001; 61(22): 8247 - 8255. [Abstract] [Full Text] [PDF]
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 E. Sadot, B. Geiger, M. Oren, and A. Ben-Ze'ev Down-Regulation of {beta}-Catenin by Activated p53 Mol. Cell. Biol., October 15, 2001; 21(20): 6768 - 6781. [Abstract] [Full Text] [PDF]
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D. F. Calvisi, V. M. Factor, R. Loi, and S. S. Thorgeirsson Activation of {beta}-Catenin during Hepatocarcinogenesis in Transgenic Mouse Models: Relationship to Phenotype and Tumor Grade Cancer Res., March 1, 2001; 61(5): 2085 - 2091. [Abstract] [Full Text]
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K. Wiechen, C. Sers, A. Agoulnik, K. Arlt, M. Dietel, P. M. Schlag, and U. Schneider Down-Regulation of Caveolin-1, a Candidate Tumor Suppressor Gene, in Sarcomas Am. J. Pathol., March 1, 2001; 158(3): 833 - 839. [Abstract] [Full Text] [PDF]
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 P. Polakis Wnt signaling and cancer Genes & Dev., August 1, 2000; 14(15): 1837 - 1851. [Full Text]
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F. T. Kolligs, B. Kolligs, K. M. Hajra, G. Hu, M. Tani, K. R. Cho, and E. R. Fearon gamma -Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta -catenin Genes & Dev., June 1, 2000; 14(11): 1319 - 1331. [Abstract] [Full Text]
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