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Detection and analysis of β‐catenin mutations in prostate cancer
Author(s) -
Chesire Dennis R.,
Ewing Charles M.,
Sauvageot Jurga,
Bova G. Steven,
Isaacs William B.
Publication year - 2000
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/1097-0045(20001201)45:4<323::aid-pros7>3.0.co;2-w
Subject(s) - prostate cancer , prostate , catenin , cancer , medicine , prostate disease , oncology , cancer research , biology , genetics , gene , wnt signaling pathway
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 interacting 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. Prostate 45:323–334, 2000. © 2000 Wiley‐Liss, Inc.