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Clinical Cancer Research Vol. 6, 460-466, February 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Altered Expression of ß-Catenin in Renal Cell Cancer and Transitional Cell Cancer with the Absence of ß-catenin Gene Mutations1

Vladimir Bilim, Takashi Kawasaki, Akiyoshi Katagiri, Shun-ji Wakatsuki, Kota Takahashi and Yoshihiko Tomita2

Department of Urology, Niigata University School of Medicine, Niigata 951, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Loss of normal ß-catenin expression and the ß-catenin gene mutations have been shown to contribute to the malignant character of various cancers. Using PCR-single-strand conformation polymorphism and DNA direct sequencing, we examined the presence of genetic alterations within the third exon of ß-catenin, which are frequently observed in other tumors, in transitional cell cancer (TCC) and renal cell cancer (RCC) cell lines, and in tumor specimens. The degrees of expression and intracellular distribution of ß-catenin were detected by immunohistochemical staining in 77 primary and 12 metastatic RCCs and in 81 primary TCCs. Western blot analysis was also applied to confirm the degree of ß-catenin expression in the cell lines and some tumor samples. We failed to reveal any genetic alterations, at least in the third exon of the ß-catenin gene, in RCC and TCC. Reduced membranous immunoreactivity of ß-catenin was observed in portions of RCC (15.5%) and TCC (24.7%) and was correlated with advanced stages and nodal involvement in RCC and with advanced stages and multiple tumors in TCC. Within the power limitations of this small study, ß-catenin abnormal expression was not correlated with recurrence or survival in either RCC or TCC. Interstitial deletions and mutations in the third exon of ß-catenin do not play a significant role in RCC or TCC tumorigenesis. Down-regulation of normal ß-catenin expression might contribute to the malignant character of RCC and TCC and result in tumor progression. However, this event is not an independent prognostic factor for recurrence or tumor specific survival.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The catenins are a family of cytoplasmic proteins that were originally identified by their association with the cell adhesion molecule E-cadherin (1, 2, 3) . ß-Catenin is one of the components of the submembranal plaque of adherens junctions and desmosomes in mammalian cells. The ß-catenin gene was mapped to band p21 on the short arm of human chromosome 3 (4) . A lack of catenin expression (5 , 6) and increased phosphorylation of ß-catenin (7) have been reported to induce the disruption of E-cadherin-mediated cell-cell attachment, even if the presence of normal E-cadherin is maintained. Previously, we demonstrated that a loss of E-cadherin expression correlated with advanced stages of RCC,3 and Kaplan-Meyer analysis showed better prognosis in the group with preserved E-cadherin than without E-cadherin detected by immunohistochemical staining (8) . Using tissue samples and cell lines, we detected that a loss of E-cadherin function was also associated with the invasive phenotype in TCC (9) .

ß-Catenin can associate with the product of the tumor suppressor gene APC that is linked to human colon cancer via the central region of APC. Mutant APC proteins have reduced affinity or no affinity for ß-catenin (10 , 11) . Recently, it was shown that ß-catenin interacts with Tcf and lymphoid enhancer factor transcription factors. These transcription factors transactivate target genes only when associated with ß-catenin. In the presence of APC, ß-catenin is removed from hTcf-4, a human homologue of Tcf-1, and transcriptional transactivation is abrogated. Thus, wild type APC can suppress signaling by the ß-catenin-Tcf complex (12) .

In colon cancer, melanoma, prostate cancer (13, 14, 15) , and some other cancers, ß-catenin can be stabilized by missense mutations in Ser33, Ser37, Thr41, and Ser45. Usually, mutations affect serine or threonine, which have been implicated in the down-regulation of ß-catenin through phosphorylation by the glycogen synthase kinase-3ß in Xenopus embryos (16) . In addition, glycogen synthase kinase-3ß serine/threonine kinase interacts with APC and ß-catenin in mammalian cells (17) . Interstitial deletions in exon 3, leading to the loss of phosphorylation sites on ß-catenin, have also been reported in primary colorectal carcinomas (18) . Mutated ß-catenins have an extended half-life (14) , leading to increased transactivation of ß-catenin downstream genes. Nuclear and/or cytoplasmic localization of ß-catenin is a potential indicator of ß-catenin mutation.

To investigate whether genetic alterations and protein dysfunction of ß-catenin play an important role in the development of urological malignancies other than prostate cancer, primary and metastatic RCC and TCC were examined. Here we showed that altered expression of ß-catenin was correlated with the malignant phenotypes of RCC and TCC, whereas no ß-catenin gene mutations were detected.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tumor Samples and Cell Lines.
Immunohistochemical staining on cryostat sections was performed on 95 upper urinary tract and bladder tumor specimens from 81 patients (one specimen was obtained from each of 70 patients, 16 specimens were obtained from 8 patients, and a total of 9 specimens were obtained from the remaining 3 patients, who had multifocal tumors; in 25 patients with multifocal tumors, only one tumor was examined immunohistochemically). There were 57 male and 24 female patients; age range was from 41 to 85 years (mean, 67.42 years). Maximal follow up was 73 months, with an average of 23 months. Forty-five tumors from 32 patients and their normal tissue counterparts were subjected to PCR-SSCP of the ß-catenin gene.

We investigated 77 primary RCCs, 12 metastatic tumors (5 brain, 2 bone, 2 lung, 1 skin, 1 lymph node, and 1 adrenal), and 2 inferior vena cava thrombi from 81 patients (primary tumors were not available in 4 patients with metastasis) for ß-catenin immunoreactivity using streptavidin-biotin bridge technique on cryostat sections. Metastatic tumors from 12 patients were not available for analysis. There were 59 male and 22 female patients; age range was from 34 to 84 years (mean, 59 years). Maximal follow up was 96 months, with an average of 31 months. Twenty-seven primary RCC and 4 metastatic sites (one each of lung, brain, skin, and lymph node) and their normal tissue counterparts were subjected to PCR-SSCP of the the ß-catenin gene.

Histological examination was performed on H&E-stained sections. Pathological staging was determined according to the TNM classification of malignant tumors. Pathological grades were assigned according to a system developed by the Japanese Urological Association based on the degree of atypia of tumor cells. The tumors were classified as low- (G1), moderate- (G2), or high-(G3) grade.

Four established bladder cancer cell lines, SCaBER, T24, HT1376, and RT4, were described earlier (19) . The RCC cell lines ACHN, Caki1, Caki2, A498, KH39, KRC/Y, and A704 were also described earlier (20) . Hematological malignancy cell lines were kindly provided by Dr. Klas G. Wiman (Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden). All cell lines were subjected to Western blot and PCR-SSCP analysis.

Immunohistochemistry and Immunoblotting.
Anti-ß-catenin or anti-E-cadherin monoclonal antibody (Transduction Laboratories, Lexington, KY) was applied for immunohistochemical staining and Western blot analysis. For immunostaining, we used the streptavidin-biotin bridge method on cryostat sections, as described previously (8) . Staining was classified as normal if the pattern of immunoreactivity was identical to that of normal tissues (distal tubules and normal urothelium) or as abnormal if the pattern was divided into diffuse (less than 90% positive tumor cells) and decreased (homogenous in more than 90% of the tumor cells, but weaker than normal epithelial cells) areas. Immunoblotting was performed as described previously (20) . Biotin-streptavidin-horseradish peroxidase complexes were detected using an ECL Western blotting kit (Amersham Pharmacia Biotech, Little Chalfont, United Kingdom) according to the manufacturer’s instructions.

DNA Extraction, PCR-SSCP, and Sequence Analysis.
High molecular weight DNA was isolated from the tumor tissue samples according to the method of Blin and Stanford (21) . Human peripheral blood DNA or human normal kidney and bladder DNA were used as the normal control. All samples subjected to gene status analysis were screened for genetic alterations by PCR and further SSCP of the ß-catenin exon 3. DNA was amplified by PCR using a sense primer (5'-AAAGCGGCTGTTAGTCACTGG-3') and an antisense primer (5'-GACTTGGGAGGTATCCACATCC-3'), corresponding to nucleotides 255–275 and 366–387, respectively. For SSCP analysis, the PCR mixture, 50 µl in volume, containing 0.05 pmol of a sense primer labeled with Fam fluorescent dye, 0.05 pmol of an antisense primer labeled with Hex fluorescent dye, 2 µl of recovered PCR product, 2.5 units of Taq polymerase (Perkin-Elmer Japan Applied Biosystems, Chiba, Japan), 5.0 µl of 10x PCR buffer, and 40 nM deoxynucleotide mix (daTP, dgTP, dtTP, and dcTP) was amplified at 30 cycles. Analysis was performed on ABI Prism 310 Genetic Analyzer (Perkin-Elmer Japan Applied Biosystems) using the fragment analysis protocol (SSCP) according to the manufacturer’s instructions.

The nucleotide sequence of the PCR products was directly determined on an ABI Prism 310 genetic analyzer. Labeling was performed with PCR primer and a BigDye Terminator RR mix (Perkin-Elmer Japan Applied Biosystems). Each sequence was verified in both the sense and antisense directions.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
All TCC and RCC cell lines and tumor specimens examined showed various levels of ß-catenin protein detected by immunoblotting (Figs. 1Citation and 2)Citation . The decrease of ß-catenin expression among the four bladder cancer cell lines detected by Western blot was observed only in RT4, and the decrease of {alpha}-catenin expression was observed only in T24 and SCaBER. E-cadherin was not detected in T24 or SCaBER (Fig. 1)Citation . In the RCC cell lines, a decreased amount of ß-catenin was observed in four of seven cell lines examined, {alpha}-catenin in seven of seven, and E-cadherin in five of six (Fig. 2)Citation .



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  		Fig. 1. Immunoblotting for 120-kDa E-cadherin, 102-kDa {alpha}-catenin, and 92-kDa ß-catenin of bladder cancer cell lines. The MCF7 breast cancer cell line was used as a positive control, and the Namalwa lymphoid cell line was used as a negative control. Bands of 46 kDa represent signals of ß-actin as a control for loading.

 


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  		Fig. 2. Immunoblotting for 120-kDa E-cadherin, 102-kDa {alpha}-catenin, and 92-kDa ß-catenin of renal cancer cell lines, normal kidney, and RCC, respectively. The MCF7 breast cancer cell line was used as a positive control, and the Namalwa lymphoid cell line was used as a negative control. RT78, grade 1, pT2 RCC; RT99, grade 1, pT3 RCC. Bands of 46 kDa represent signals of ß-actin as a control for loading.

 
Immunohistochemical staining was performed to analyze the localization and accumulation of ß-catenin in the cells. Homogenous strong membranous immunoreactivity was detected in all normal urothelium specimens. In normal kidney, proximal and distal tubules and some mesangial cells of the glomeruli showed a uniform expression of ß-catenin on the cell surfaces (Fig. 3)Citation . In all RCCs and TCCs examined, we failed to find overexpression of ß-catenin with cytoplasmic and/or nuclear immunoreactivity.



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  		Fig. 3. ß-Catenin expression in the normal urothelium, TCC, normal kidney, and RCC. Normal transitional epithelium of the urinary tract shows strong membranous immunoreactivity (A). Noninvasive grade 1 tumor of the bladder shows preserved ß-catenin expression (C). Decreased expression of ß-catenin was seen in invasive, stage 3, grade 3 TCC (E). A gradient of ß-catenin expression was seen in TCC, in which invasive part of the tumor loses normal membranous ß-catenin staining (G). In normal kidney (B), ß-catenin was detected on the cell membranes of renal tubules (*, glomerulus). A primary lesion of stage 1, grade 1 RCC (D) has homogenous membranous expression of ß-catenin. A lack of ß-catenin immunoreactivity was seen in stage 3, grade 3 RCC (F). Scale bars, 75 µm.

 
Among the 81 primary TCCs, 6 (7.4%) showed diffuse and 14 (17.3%) uniformly decreased staining (Table 1Citation and Fig. 3Citation ). In TCC, loss of ß-catenin was correlated only with tumor stage >3 (P < 0.05; {chi}2 = 5.2) and multiplicity of tumors (P <<0.01; {chi}2 = 10) but was not correlated with either tumor grade, lymph node involvement, or metastasis to distant organs. Correlation between ß-catenin and E-cadherin status was not observed. Among the 32 samples examined immunohistochemically for both proteins, 17 showed normal staining patterns of ß-catenin and E-Cadherin, 14 had abnormal staining of one of the proteins, and only 1 demonstrated decreased immunoreactivity for both proteins.


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  		Table 1 Relationship between ß-catenin expression on TCC and clinicopathological characteristics

 
Among the 77 primary RCCs, 8 (10.3%) showed diffuse and 4 (5.2%) uniformly decreased staining (Table 2Citation and Fig. 3Citation ). Taken together, the expression of ß-catenin was disturbed only in 15.5% of RCC. Loss of ß-catenin was correlated with tumor stage >3 (P < 0.05, {chi}2=4.8) and nodal metastasis (p<<0.05, {chi}2=5.86). Preserved ß-catenin staining correlated with tumor grade 1 (P = 0.005; {chi}2 = 7.8). Only 3 of 12 metastatic RCC showed decreased expression of ß-catenin, and there was no correlation between loss of ß-catenin immunoreactivity and the presence of distant metastasis in this study (Table 3)Citation . Two inferior vena cava tumor thrombi were highly positive for ß-catenin.


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  		Table 2 Relationship between ß-catenin expression on RCC and clinicopathological characteristics

 

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  		Table 3 ß-Catenin expression in RCC metastasis

Among 12 metastatic RCC studied by immunohistochemistry, 8 primary tumor tissues were available for immunohistochemical examination, all of which demonstrated preserved membranous pattern of ß-catenin immunoreactivity.

 
Fifty-two RCC samples were stained for both ß-catenin and E-cadherin. A loss of normal E-cadherin staining patterns was observed in 46 of the 52 samples (88.5%). Although there was no statistically significant correlation between loss of ß-catenin and E-cadherin expression, all six samples with normal E-cadherin staining patterns showed normal ß-catenin expression. On the other hand, all 12 samples with altered ß-catenin staining also had abnormal E-cadherin staining. Thus, it is possible that the down-regulation of E-Cadherin is essential for ß-catenin dysfunction at least in RCC.

Median Kaplan-Meyer estimates of the disease-specific survival and recurrence-free survival for patients with normal and abnormal ß-catenin immunohistochemical staining were not significantly different by the log rank test in TCC and RCC.

To detect genomic rearrangements (deletions in exon 3), we performed PCR with the primer pair corresponding to the nucleotide sequences in exon 3. Fragments of the expected size (133 bp) could be amplified from all specimens used.

On PCR-SSCP analysis, aberrant or shifted peaks in comparison with normal control were not detected in any individual or cell line examined. The absence of ß-catenin mutations in the third exon was confirmed by direct sequencing of the PCR products (Fig. 4)Citation .



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  		Fig. 4. Sequencing analysis of DNA from normal tissue (A) and the SCaBER TCC cell line (B). C, PCR-SSCP analysis of the ß-catenin gene in normal bladder and TCC cell lines SCaBER, T24, HT1376, and RT4. No loss of heterozygosity or mobility shift was detected in any of the specimens.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although ß-catenin was originally discovered as a cadherin-binding protein, it has recently been shown to function as a transcriptional activator when complexed with members of the Tcf family of DNA binding proteins (22 , 23) . Previous studies have revealed that a single amino acid change resulting from missense mutation or interstitial deletions in the third exon of the ß-catenin gene results in ß-catenin accumulation, translocation to the nucleus, and promotion of carcinogenic changes of the cell (12, 13, 14 , 18) . Such genomic rearrangements result in the loss of phosphorylating sites on ß-catenin, with subsequent accumulation of the protein and activation of signal transduction. To our knowledge, the present study is the first report on the genetic status of ß-catenin in TCC and RCC. We did not detect any genetic rearrangements of ß-catenin in 31 RCC and 45 TCC samples. However, to rule out whether the Tcf/lymphoid enhancer factor signaling pathway is not disrupted in RCC and TCC and whether components other than ß-catenin are deregulated in urological malignancies, additional investigations are deemed to be necessary.

There are discrepancies concerning the degree of ß-catenin alteration and its significance for the malignant character of TCC and RCC in the previous reports. Thus, Shimazui et al. (24) have shown that the decreased expression of ß-catenin, E-cadherin, and {alpha}-catenin is associated with poor survival and that these three molecules have a very similar prognostic value in the case of TCC. On the other hand, Syrigos et al. (25) showed that only E-cadherin and {gamma}-catenin expression correlated with survival in TCC. Our study, including a larger number of TCC patients [81 versus 48 in the study of Shimazui et al. (24) and 68 in that of Syrigos et al. (25) ] and a longer follow-up period (maximum of 73 months versus 60 months in both previous studies), was unable to reveal any statistically significant correlation between ß-catenin immunoreactivity and survival. Loss of normal membranous ß-catenin expression was reported in 39.5% by Shimazui et al. (24) on cryostat sections and in 83% by Syrigos et al. (25) on paraffin-embedded sections. Here, we report 24.7% of abnormal immunoreactivity using cryostat sections. Although an infrequently observed event in our series, ß-catenin aberrant staining correlated with an advanced tumor grade and stage.

The high recurrence rate of TCC is thought to be caused by shedding and subsequent implantation of tumor cells in the urinary tract, usually occurring downstream of the original tumor. A strong correlation between the altered expression of ß-catenin and multiple tumors was detected in the present study. This finding supports the assumption that dysfunction of the cadherin-catenin complex, with consequent disruption of intercellular interactions, is crucial for recurrence of TCC. Moreover, of 4 of the 11 cases examined with multifocal TCC, tumors located upstream in the urinary tract showed abnormal ß-catenin immunoreactivity, whereas downstream tumors presented with normal membranous staining. This has been shown for some adhesion molecules, when their function is deteriorated in original tumor and restored on the metastatic site, where microenvironmental factors favor the adhesion.

In a recently published article (26) , ß-catenin aberrant expression was observed in 35.5% (32 of 90) of RCCs, and a significant correlation between ß-catenin expression and survival was found; this value was twice that reported in the present study. We were unable to confirm that finding.

The absence of correlation between ß-catenin and distant metastasis, as well as the fact that decreased ß-catenin immunoreactivity was detected only in a few cases of metastases, might prove that sole ß-catenin dysfunction is insufficient to trigger a metastatic process. Deregulation of other compounds of the cadherin-catenin complexes are more important for metastasization to distant organs. However, we found a correlation between loss of normal ß-catenin staining pattern in RCC and lymph node metastasis. Although the number of the cases with distant metastasis or lymph node involvement is not large (2 and 5 in TCC and 18 and 6 in RCC, respectively) the tendency is that loss of ß-catenin facilitates metastasization through the lymphatic system. To draw a definite conclusion, a study of a larger number of cases with metastasis is necessary.

ß-Catenin plays essential roles in both intercellular adhesion and signal transduction, which are believed to be two independent functions of ß-catenin. Here, we showed that ß-catenin gene mutations do not take place in TCC or RCC tumorogenesis, although abnormal ß-catenin immunoreactivity was observed in some TCC and RCC, which may hamper cell adhesion and lead to invasion and metastasis.

In conclusion, although it is a relatively rare event, deterioration of ß-catenin normal membranous immunoreactivity correlates with a high grade and advanced stage in TCC and RCC. Moreover, correlation has been observed with multiple tumors in TCC. To estimate the significance for survival, additional studies with larger numbers of patients and longer follow-up periods are warranted.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan. V. B. is the recipient of fellowship from the Japan Society for the Promotion of Science. Back

2 To whom requests for reprints should be addressed, at Department of Urology, Niigata University School of Medicine, Asahimachi 1, Niigata 951, Japan. Phone: 81-25-227-2285; Fax: 81-25-227-0784; E-mail: ytomita{at}med.niigata-u.ac.jp Back

3 The abbreviations used are: RCC, renal cell cancer; TCC, transitional cell cancer; SSCP, single-strand conformation polymorphism; APC, adenomatous polyposis coli; Tcf, T cell factor. Back

Received 7/30/99; revised 11/ 1/99; accepted 11/ 3/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Ozawa M., Baribault H., Kemler R. The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J., 8: 1711-1717, 1989.[Medline]
  2. Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genetics, 9: 317-321, 1993.[CrossRef][Medline]
  3. Piepenhagen P., Nelson W. Defining E-cadherin-associated protein complexes in epithelial cells: plakoglobin, ß- and {gamma}-catenin are distinct components. J. Cell Sci. (Washington DC), 104: 751-762, 1993.[Abstract]
  4. Kraus C., Liehr T., Hulsken J., Behrens J., Birchmeier W., Grzeschik K., Ballhausen W. Localization of the human ß-catenin gene (CTNNB1) to 3p21: a region implicated in tumor development. Genomics, 23: 271-274, 1994.
  5. Hirano S., Kimoto N., Shimoyama Y., Hirohashi S., Takeichi M. Identification of neural {alpha}-catenin as a key regulator of cadherin function and multicellular organization. Cell, 70: 293-301, 1992.[CrossRef][Medline]
  6. Shimoyama Y., Nagafuchi A., Fujita S., Gotoh M., Takeichi M., Tsukita S., Hirohashi S. Cadherin dysfunction in a human cancer cell line: possible involvement of loss of {alpha}-catenin expression in reduced cell-cell adhesiveness. Cancer Res., 52: 5770-5774, 1992.[Abstract/Free Full Text]
  7. Behrens J., Vakaet L., Friis R., Winterhager E., van Roy F., Mareel M., Birchmeier W. Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/ß-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J. Cell Biol., 120: 757-766, 1993.[Abstract/Free Full Text]
  8. Katagiri A., Watanabe R., Tomita Y. E-cadherin expression in renal cell cancer and its significance in metastasis and survival. Br. J. Cancer, 71: 376-379, 1995.[Medline]
  9. Wakatsuku S., Watanabe R., Saito K., Saito T., Katagiri A., Sato S., Tomita Y. Loss of human E-cadherin (ECD) correlated with invasiveness of transitional cell cancer in the renal pelvis, ureter and urinaru bladder. Cancer Lett., 103: 11-17, 1996.[CrossRef][Medline]
  10. Rubinfeld B., Souza B., Albert I., Muller O., Chamberlain S., Masiarz F., Munemitsu S., Polakis P. Association of the APC gene product with ß-catenin. Science (Washington DC), 262: 1731-1734, 1993.[Abstract/Free Full Text]
  11. Su L., Vogelstein B., Kinzler K. Association of the APC tumor suppressor protein with catenins. Science (Washington DC), 262: 1734-1737, 1993.[Abstract/Free Full Text]
  12. Korinek V., Barker N., Morin P., van Wichen D., de Weger R., Kinzler K., Vogelstein B., Clevers H. Constitutive transcriptional activation by a ß-catenin-Tcf complex in APC -/- colon carcinoma. Science (Washington DC), 275: 1784-1787, 1997.[Abstract/Free Full Text]
  13. Morin P. J., Sparks A. B., Korinek V., Barker N., Clevers H., Vogelstein B., Kinzler K. W. Activation of ß-catenin-Tcf signaling in colon cancer by mutations in ß-catenin or APC. Science (Washington DC), 275: 1787-1790, 1997.[Abstract/Free Full Text]
  14. Rubinfeld B., Robbins P., El-Gamil M., Albert I., Porfiri E., Polakis P. Stabilization of ß-catenin by genetic defects in melanoma cell lines. Science (Washington DC), 275: 1790-1792, 1997.[Abstract/Free Full Text]
  15. Voeller H. J., Truica C. I., Gelmann E. P. ß-Catenin mutations in human prostate cancer. Cancer Res., 58: 2520-2523, 1998.[Abstract/Free Full Text]
  16. Yost C., Torres M., Miller J. R., Huang E., Kimelman D., Moon R. T. The axis-inducing activity, stability, and subcellular distribution of ß-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev., 10: 1443-1454, 1996.[Abstract/Free Full Text]
  17. Rubinfeld B., Albert I., Porfiri E., Fiol C., Munemitsu S., Polakis P. Binding of GSK3ß to the APC-ß-catenin complex and regulation of complex assembly. Science (Washington DC), 272: 1023-1026, 1996.[Abstract]
  18. Iwao K., Nakamori S., Kameyama M., Imaoka S., Kinoshita M., Fukui T., Ishiguro S., Nakamura Y., Miyoshi Y. Activation of the ß-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res., 58: 1021-1026, 1998.[Abstract/Free Full Text]
  19. Kawasaki T., Tomita Y., Watanabe R., Tanikawa T., Kumanishi T., Sato S. mRNA and protein expression of p53 mutations in human bladder cancer cell lines. Cancer Lett., 82: 113-121, 1994.[CrossRef][Medline]
  20. Tomita Y., Bilim V., Kawasaki T., Takahashi K., Okan I., Magnusson K. Frequent expression of Bcl-2 in renal-cell-carcinomas carrying wild-type p53. Int. J. Cancer, 66: 322-325, 1996.[CrossRef][Medline]
  21. Blin N., Stafford D. A general method for isolation of high molecular weight DNA from eucaryotes. Nucleic Acids Res., 3: 2303-2308, 1976.
  22. Molenaar M., van de Wetering M., Oosterwegel M., Peterson-Maduro J., Godsave S., Korinek V., Roose J., Destree O., Clevers H. XTcf-3 transcription factor mediates ß-catenin-induced axis formation in Xenopus embryos. Cell., 86: 391-399, 1996.[CrossRef][Medline]
  23. Behrens J., von Kries J. P., Kuhl M., Bruhn L., Wedlich D., Grosschedl R., Birchmeier W. Functional interaction of ß-catenin with the transcription factor LEF-1. Nature (Lond.)., 382: 638-642, 1996.[CrossRef][Medline]
  24. Shimazui T., Schalken J. A., Giroldi L. A., Jansen C. F., Akaza H., Koiso K., Debruyne F. M., Bringuier P. P. Prognostic value of cadherin-associated molecules ({alpha}-, ß-, and {gamma}-catenins and p120cas) in bladder tumors. Cancer Res., 56: 4154-4158, 1996.[Abstract/Free Full Text]
  25. Syrigos K. N., Harrington K., Waxman J., Krausz T., Pignatelli M. Altered {gamma}-catenin expression correlates with poor survival in patients with bladder cancer. J. Urol., 160: 1889-1893, 1998.[CrossRef][Medline]
  26. Shimazui T., Bringuier P. P., van Berkel H., Ruijter E., Akaza H., Debruyne F. M., Oosterwijk E., Schalken J. A. Decreased expression of {alpha}-catenin is associated with poor prognosis of patients with localized renal cell carcinoma. Int. J. Cancer, 74: 523-528, 1997.[CrossRef][Medline]



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J R Toro, Y O Shevchenko, J G Compton, and S J Bale
Exclusion of PTEN, CTNNB1, and PTCH as candidate genes for Birt-Hogg-Dube syndrome
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