Detection and analysis of ?-catenin mutations in prostate cancer

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

doi:10.1002/1097-0045(20001201)45:4<323::aid-pros7>3.0.co;2-w

Cited by 164 publications

(122 citation statements)

References 39 publications

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“…With these ideas in mind, we wished to examine facets of b-catenin signaling in CaP cells to evaluate its contribution to disease progression in vivo. Results shown here, along with previous work (Chesire et al, 2000), directly implicate b-catenin as a potential nuclear signaling factor in both neoplastic and rapidly dividing normal prostate epithelium. The function of bcatenin as a transactivator of TCF target gene activity b-catenin signaling in prostate DR Chesire et al to drive cell proliferation is well established.…”

Section: Introductionsupporting

confidence: 80%

“…Previous work and data presented herein implicate the wnt pathway and its e ector signaling molecule, b-catenin, in this disease (Chesire et al, 2000;Voeller et al, 1998). b-catenin mutations were detected at a rate of *5 ± 7% and shown to result in its accumulation and nuclear localization.…”

Section: Introductionsupporting

confidence: 60%

“…Previously, we had performed a mutation screen of bcatenin exon 3 and found activating mutations in primary cases (*5%) and one metastatic case (Chesire et al, 2000). Immunostaining of these tumors demonstrated nuclear localization of b-catenin, suggesting that these mutations imparted greater signaling and CRT.…”

Section: Nuclear Localization Of B-catenin In Prostate Cellsmentioning

confidence: 97%

“…To better understand the mode(s) of signaling b-catenin orchestrates, we analysed its activity in the contexts of either TCF-or AR-based target gene expression Truica et al, 2000). Certain CaP cell lines are capable of supporting b-catenin nuclear translocation and TCF-based CRT, as shown by immuno¯uorescence and reporter studies (Chesire et al, 2000). We determined the fold activation of a synthetic b-catenin/TCF-responsive luciferase reporter (pOT) upon ectopic expression of wild type or mutant (Del, D24-47) b-catenin in a broader array of CaP cell lines ( Figure 3a).…”

Section: B-catenin Signaling Through Tcf Transactivationmentioning

confidence: 99%

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In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis

Chesire¹,

Ewing²,

et al. 2002

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Understanding the molecular etiology of prostate cancer (CaP) progression is paramount for broadening current diagnostic and therapeutic modalities. Current interest in the role of wnt pathway signaling in prostate tumorigenesis was generated with the ®nding of b-catenin mutation and corresponding nuclear localization in primary lesions. The recent ®nding of b-catenin-induced enhancement of androgen receptor (AR) function potentially ties b-catenin to key regulatory steps of prostate cell growth, di erentiation, and transformation. By immunohistological analysis of metastatic tumors, we detected nuclear bcatenin in 20% of lethal CaP cases, suggesting a more common role for b-catenin in advanced disease than would be predicted by its mutation rate. Interestingly, bcatenin nuclear localization was found to occur concomitantly with androgen-induced regrowth of normal rat prostate. These in vivo observations likely implicate b-catenin involvement in both normal and neoplastic prostate physiology, thus prompting our interest in further characterizing modes of b-catenin signaling in prostate cells. Extending our previous ®ndings, we demonstrate that transient b-catenin over-expression stimulates T cell factor (TCF) signaling in most CaP cell lines. Further, this activity is not subject to crossregulation by phosphoinositide-3-kinase (PI3-K)/Akt signaling, a stimulatory pathway often upregulated in CaP upon PTEN inactivation. Consistent with a previous report, we observed that transient b-catenin overexpression enhances AR-mediated transcription o two natural target gene promoters. However, we were unable to recapitulate b-catenin-induced stimulation of ectopically expressed AR in AR-negative cells, suggesting that other AR-associated factors are required for this activity. Although LNCaP cells are capable of this mode of AR co-stimulation, stable expression of mutant b-catenin did not alter their proliferative response to androgen. In total, our characterization of b-catenin signaling in CaP reveals the complex nature of its activity in prostate tissue, indicating that b-catenin potentially contributes to multiple stimulatory inputs required for disease progression.

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Section: Introductionsupporting

confidence: 80%

Section: Introductionsupporting

confidence: 60%

Section: Nuclear Localization Of B-catenin In Prostate Cellsmentioning

confidence: 97%

Section: B-catenin Signaling Through Tcf Transactivationmentioning

confidence: 99%

See 2 more Smart Citations

In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis

Chesire¹,

Ewing²,

et al. 2002

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“…Increasing evidence also indicates that the Wnt signaling pathway plays a role in PCa, especially in progression to the most aggressive and therapeutic-resistant state (de la Taille et al, 2003;Chen et al, 2004b). Mutations in both APC (Watanabe et al, 1996) and b-catenin (Voeller et al, 1998;Chesire et al, 2000) have been described in human PCa specimens, however, their apparent occurrence is at too low a frequency to account for the evidence for more frequent activation of Wnt signaling in this tumor system. Recently, we provided evidence that a novel member of the protocadherin gene family, protocadherin-PC (PCDH-PC) is upregulated in apoptosis-and hormone-resistant human PCa cells and that a major effect of this gene product is the upregulation of Wnt signaling (Yang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells

et al. 2006

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WntSignal Transduction

Ilyas

2007

The Cancer Handbook

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Disruption of Wnt signalling is commonly found in a wide range of cancers and thus can possibly be regarded as a “generic” step in the process of carcinogenesis. Recent advances in the understanding of the Wnt signalling pathway have given insight into how inappropriate activation of this pathway may facilitate the neoplastic conversion of a normal cell. In addition, identification of the mechanisms which regulate Wnt signalling has led to the possibility of manipulating these mechanisms in order to down‐regulate Wnt signalling as a therapeutic strategy. In this chapter, the role of aberrant Wnt signalling in the mechanics of tumour development is discussed together with its implications for anti‐tumour therapy.

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Detection and analysis of ?-catenin mutations in prostate cancer

Cited by 164 publications

References 39 publications

In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis

In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis

Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells

WntSignal Transduction

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