Detection and analysis of β-catenin mutations in prostate cancer

Dennis R. Chesire, Charles M. Ewing, Jurga Sauvageot, G. Steven Bova, William B Isaacs

Research output: Contribution to journalArticle

Abstract

BACKGROUND. E-cadherin and α-catenin are components of adherens junctions which mediate calcium-dependent, cell-cell adhesion in a homotypic manner. Both these molecules have been defined as useful tumor markers as their altered expression correlates with increased tumor aggressiveness and dedifferentiation. More recently, alterations of a third component of adherens junctions, β-catenin, have been observed to play a role in several human cancers. Dysregulation of β-catenin, either by direct mutation or by defects in inter-acting pathways/regulators, can result in its cytoplasmic accumulation and nuclear translocation. In the nucleus, β-catenin forms a transcriptional complex capable of upregulating target genes, many of which encode proliferative factors. Given its oncogenic activity and connection to human cancer, we examined the β-catenin gene and its expression in prostate cancer. METHODS. By single-stranded conformational polymorphism (SSCP) and DNA sequencing analyses, we screened exon 3 of β-catenin from a panel of 81 primary tumors obtained at radical prostatectomy, 22 lymph node metastases from untreated patients, and a unique set of 61 metastatic tissues from 19 patients who died of hormone-refractory disease. RESULTS. We found putative activating mutations (missense and deletion) at a rate of 5% (7/138). One patient had the same 72 base pair deletion in each of nine separate metastases examined, indicating that this change was associated with a clonal population of metastatic cells. CONCLUSIONS. Immunohistological staining of mutation-positive tumors demonstrated β-catenin accumulation and nuclear localization in a heterogeneous fashion. Consistent with this in vivo finding, our in vitro analyses demonstrate that certain mutations can result in increased β-catenin nuclear activity in prostate cancer cell lines. These data implicate the β-catenin signaling pathway in the development of a subset of prostate cancers. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)323-334
Number of pages12
JournalProstate
Volume45
Issue number4
DOIs
StatePublished - 2000

Fingerprint

Catenins
Prostatic Neoplasms
Mutation
Adherens Junctions
Neoplasms
Neoplasm Metastasis
Single-Stranded Conformational Polymorphism
Sequence Deletion
Single-Stranded DNA
Missense Mutation
Cadherins
Tumor Biomarkers
Prostatectomy
DNA Sequence Analysis
Cell Adhesion
Base Pairing
Exons
Lymph Nodes
Hormones
Staining and Labeling

Keywords

  • β-Catenin
  • Activating mutation
  • Prostate cancer
  • wnt Pathway

ASJC Scopus subject areas

  • Urology

Cite this

Detection and analysis of β-catenin mutations in prostate cancer. / Chesire, Dennis R.; Ewing, Charles M.; Sauvageot, Jurga; Steven Bova, G.; Isaacs, William B.

In: Prostate, Vol. 45, No. 4, 2000, p. 323-334.

Research output: Contribution to journalArticle

Chesire, Dennis R. ; Ewing, Charles M. ; Sauvageot, Jurga ; Steven Bova, G. ; Isaacs, William B. / Detection and analysis of β-catenin mutations in prostate cancer. In: Prostate. 2000 ; Vol. 45, No. 4. pp. 323-334.
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abstract = "BACKGROUND. E-cadherin and α-catenin are components of adherens junctions which mediate calcium-dependent, cell-cell adhesion in a homotypic manner. Both these molecules have been defined as useful tumor markers as their altered expression correlates with increased tumor aggressiveness and dedifferentiation. More recently, alterations of a third component of adherens junctions, β-catenin, have been observed to play a role in several human cancers. Dysregulation of β-catenin, either by direct mutation or by defects in inter-acting pathways/regulators, can result in its cytoplasmic accumulation and nuclear translocation. In the nucleus, β-catenin forms a transcriptional complex capable of upregulating target genes, many of which encode proliferative factors. Given its oncogenic activity and connection to human cancer, we examined the β-catenin gene and its expression in prostate cancer. METHODS. By single-stranded conformational polymorphism (SSCP) and DNA sequencing analyses, we screened exon 3 of β-catenin from a panel of 81 primary tumors obtained at radical prostatectomy, 22 lymph node metastases from untreated patients, and a unique set of 61 metastatic tissues from 19 patients who died of hormone-refractory disease. RESULTS. We found putative activating mutations (missense and deletion) at a rate of 5{\%} (7/138). One patient had the same 72 base pair deletion in each of nine separate metastases examined, indicating that this change was associated with a clonal population of metastatic cells. CONCLUSIONS. Immunohistological staining of mutation-positive tumors demonstrated β-catenin accumulation and nuclear localization in a heterogeneous fashion. Consistent with this in vivo finding, our in vitro analyses demonstrate that certain mutations can result in increased β-catenin nuclear activity in prostate cancer cell lines. These data implicate the β-catenin signaling pathway in the development of a subset of prostate cancers. (C) 2000 Wiley-Liss, Inc.",
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T1 - Detection and analysis of β-catenin mutations in prostate cancer

AU - Chesire, Dennis R.

AU - Ewing, Charles M.

AU - Sauvageot, Jurga

AU - Steven Bova, G.

AU - Isaacs, William B

PY - 2000

Y1 - 2000

N2 - BACKGROUND. E-cadherin and α-catenin are components of adherens junctions which mediate calcium-dependent, cell-cell adhesion in a homotypic manner. Both these molecules have been defined as useful tumor markers as their altered expression correlates with increased tumor aggressiveness and dedifferentiation. More recently, alterations of a third component of adherens junctions, β-catenin, have been observed to play a role in several human cancers. Dysregulation of β-catenin, either by direct mutation or by defects in inter-acting pathways/regulators, can result in its cytoplasmic accumulation and nuclear translocation. In the nucleus, β-catenin forms a transcriptional complex capable of upregulating target genes, many of which encode proliferative factors. Given its oncogenic activity and connection to human cancer, we examined the β-catenin gene and its expression in prostate cancer. METHODS. By single-stranded conformational polymorphism (SSCP) and DNA sequencing analyses, we screened exon 3 of β-catenin from a panel of 81 primary tumors obtained at radical prostatectomy, 22 lymph node metastases from untreated patients, and a unique set of 61 metastatic tissues from 19 patients who died of hormone-refractory disease. RESULTS. We found putative activating mutations (missense and deletion) at a rate of 5% (7/138). One patient had the same 72 base pair deletion in each of nine separate metastases examined, indicating that this change was associated with a clonal population of metastatic cells. CONCLUSIONS. Immunohistological staining of mutation-positive tumors demonstrated β-catenin accumulation and nuclear localization in a heterogeneous fashion. Consistent with this in vivo finding, our in vitro analyses demonstrate that certain mutations can result in increased β-catenin nuclear activity in prostate cancer cell lines. These data implicate the β-catenin signaling pathway in the development of a subset of prostate cancers. (C) 2000 Wiley-Liss, Inc.

AB - BACKGROUND. E-cadherin and α-catenin are components of adherens junctions which mediate calcium-dependent, cell-cell adhesion in a homotypic manner. Both these molecules have been defined as useful tumor markers as their altered expression correlates with increased tumor aggressiveness and dedifferentiation. More recently, alterations of a third component of adherens junctions, β-catenin, have been observed to play a role in several human cancers. Dysregulation of β-catenin, either by direct mutation or by defects in inter-acting pathways/regulators, can result in its cytoplasmic accumulation and nuclear translocation. In the nucleus, β-catenin forms a transcriptional complex capable of upregulating target genes, many of which encode proliferative factors. Given its oncogenic activity and connection to human cancer, we examined the β-catenin gene and its expression in prostate cancer. METHODS. By single-stranded conformational polymorphism (SSCP) and DNA sequencing analyses, we screened exon 3 of β-catenin from a panel of 81 primary tumors obtained at radical prostatectomy, 22 lymph node metastases from untreated patients, and a unique set of 61 metastatic tissues from 19 patients who died of hormone-refractory disease. RESULTS. We found putative activating mutations (missense and deletion) at a rate of 5% (7/138). One patient had the same 72 base pair deletion in each of nine separate metastases examined, indicating that this change was associated with a clonal population of metastatic cells. CONCLUSIONS. Immunohistological staining of mutation-positive tumors demonstrated β-catenin accumulation and nuclear localization in a heterogeneous fashion. Consistent with this in vivo finding, our in vitro analyses demonstrate that certain mutations can result in increased β-catenin nuclear activity in prostate cancer cell lines. These data implicate the β-catenin signaling pathway in the development of a subset of prostate cancers. (C) 2000 Wiley-Liss, Inc.

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