APC/CTNNB1 (β‐catenin) pathway alterations in human prostate cancers

Genetic alterations serve as beacons for the involvement of specific pathways in tumorigenesis. It was previously shown that 5% of prostate tumors harbor CTNNB1 mutations, suggesting that this tumor type may involve a deregulated APC/CTNNB1 pathway. To explore this possibility further, we searched for mutations in genes implicated in this pathway in 22 samples that included cell lines, xenografts, and primary tumors. We identified seven alterations: two in CTNNB1, three in APC, and two in hTRCP1 (also known as BTRC) which controls the degradation of CTNNB1. Alterations in the CTNNB1 regulatory domain, APC, and hTRCP1 were mutually exclusive, consistent with their equivalent effects on CTNNB1 stability. These results suggest that CTNNB1 signaling plays a critical role in the development of a significant fraction of prostate cancers. Moreover, they provide the first evidence that hTRCP1 plays a role in human neoplasia. © 2002 Wiley‐Liss, Inc.

[1]  W. Isaacs,et al.  Detection and analysis of β‐catenin mutations in prostate cancer , 2000 .

[2]  E. Gelmann,et al.  β-Catenin Mutations in Human Prostate Cancer , 1998 .

[3]  A. Sparks,et al.  Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. , 1998, Cancer research.

[4]  G. Struhl,et al.  Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb , 1998, Nature.

[5]  P. Robbins,et al.  Stabilization of beta-catenin by genetic defects in melanoma cell lines. , 1997, Science.

[6]  Y. Marikawa,et al.  β-TrCP is a negative regulator of the Wnt/β-catenin signaling pathway and dorsal axis formation in Xenopus embryos , 1998, Mechanisms of Development.

[7]  Y. Marikawa,et al.  beta-TrCP is a negative regulator of Wnt/beta-catenin signaling pathway and dorsal axis formation in Xenopus embryos. , 1998, Mechanisms of development.

[8]  R. Benarous,et al.  The F-box protein β-TrCP associates with phosphorylated β-catenin and regulates its activity in the cell , 1999, Current Biology.

[9]  E. Gelmann,et al.  Beta-catenin mutations in human prostate cancer. , 1998, Cancer research.

[10]  W. Isaacs,et al.  Detection and analysis of beta-catenin mutations in prostate cancer. , 2000, The Prostate.

[11]  John M. Maris,et al.  Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia , 1999, Nature Genetics.

[12]  T. Sugimura,et al.  APC gene mutations in human prostate cancer. , 1996, Japanese journal of clinical oncology.

[13]  Stephen J. Elledge,et al.  The SCFβ-TRCP–ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro , 1999 .

[14]  P. Polakis,et al.  Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. , 1996, Science.

[15]  T. Igarashi,et al.  State of Adenomatous Polyposis Coli Gene and ras Oncogenes in Japanese Prostate Cancer , 1994, Japanese journal of cancer research : Gann.

[16]  M. Pagano,et al.  Five human genes encoding F-box proteins: chromosome mapping and analysis in human tumors , 2000, Cytogenetic and Genome Research.

[17]  R. Vessella,et al.  Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  K. Kinzler,et al.  Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma , 1997, Science.

[19]  Z. F. Liu,et al.  Allelic loss of chromosome 18q and prognosis in colorectal cancer. , 1994, The New England journal of medicine.

[20]  M. Kitagawa,et al.  An F‐box protein, FWD1, mediates ubiquitin‐dependent proteolysis of β‐catenin , 1999, The EMBO journal.

[21]  Paul Polakis,et al.  Binding of GSK3β to the APC-β-Catenin Complex and Regulation of Complex Assembly , 1996, Science.

[22]  Bert Vogelstein,et al.  Mutational Analysis of the APC/β-Catenin/Tcf Pathway in Colorectal Cancer , 1998 .

[23]  S. Elledge,et al.  The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. , 1999, Genes & development.

[24]  K. Pienta,et al.  Rapid ("warm") autopsy study for procurement of metastatic prostate cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  K. Kinzler,et al.  Molecular diagnosis of familial adenomatous polyposis. , 1993, The New England journal of medicine.

[26]  R. Benarous,et al.  The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. , 1999, Current biology : CB.

[27]  D. Thomas,et al.  A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. , 1998, Molecular cell.

[28]  P. Polakis,et al.  Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.