Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

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

Oncogene volume 21, pages 2679–2694 (2002)Cite this article

Abstract

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 finding of β-catenin mutation and corresponding nuclear localization in primary lesions. The recent finding of β-catenin-induced enhancement of androgen receptor (AR) function potentially ties β-catenin to key regulatory steps of prostate cell growth, differentiation, and transformation. By immunohistological analysis of metastatic tumors, we detected nuclear β-catenin in 20% of lethal CaP cases, suggesting a more common role for β-catenin in advanced disease than would be predicted by its mutation rate. Interestingly, β-catenin nuclear localization was found to occur concomitantly with androgen-induced regrowth of normal rat prostate. These in vivo observations likely implicate β-catenin involvement in both normal and neoplastic prostate physiology, thus prompting our interest in further characterizing modes of β-catenin signaling in prostate cells. Extending our previous findings, we demonstrate that transient β-catenin over-expression stimulates T cell factor (TCF) signaling in most CaP cell lines. Further, this activity is not subject to cross-regulation 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 β-catenin over-expression enhances AR-mediated transcription off two natural target gene promoters. However, we were unable to recapitulate β-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 β-catenin did not alter their proliferative response to androgen. In total, our characterization of β-catenin signaling in CaP reveals the complex nature of its activity in prostate tissue, indicating that β-catenin potentially contributes to multiple stimulatory inputs required for disease progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 5
Figure 3
Figure 4
Figure 6
Figure 7

Similar content being viewed by others

References

  • Aberle H, Bauer A, Stappert J, Kispert A, Kemler R . 1997 EMBO J. 16: 3797–3804

  • Ali IU, Schriml LM, Dean M . 1999 J. Natl. Cancer Inst. 91: 1922–1932

  • Barker N, Huls G, Korinek V, Clevers H . 1999 Am. J. Pathol. 154: 29–35

  • Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, Willi N, Mihatsch MJ, Sauter G, Kallioniemi OP . 1999 Cancer Res. 59: 803–806

  • Chesire DR, Ewing CM, Sauvageot J, Bova GS, Isaacs WB . 2000 Prostate 45: 323–334

  • Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM . 1999 Oncogene 18: 2883–2891

  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA . 1995 Nature 378: 785–789

  • Cude KJ, Dixon SC, Guo Y, Lisella J, Figg WD . 1999 J. Mol. Med. 77: 419–426

  • Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A, Bartsch G, Klocker H . 1994 Cancer Res. 54: 5474–5478

  • Culig Z, Hobisch A, Hittmair A, Peterziel H, Cato AC, Bartsch G, Klocker H . 1998 Prostate 35: 63–70

  • DasGupta R, Fuchs E . 1999 Development 126: 4557–4568

  • Ding VW, Chen RH, McCormick F . 2000 J. Biol. Chem. 275: 32475–32481

  • Duval A, Rolland S, Tubacher E, Bui H, Thomas G, Hamelin R . 2000 Cancer Res. 60: 3872–3879

  • Dyer BW, Ferrer FA, Klinedinst DK, Rodriguez R . 2000 Anal. Biochem. 282: 158–161

  • Easwaran V, Pishvaian M, Salimuddin, Byers S . 1999 Curr. Biol. 9: 1415–1418

  • Elo JP, Visakorpi T . 2001 Ann. Med. 33: 130–141

  • Grad JM, Dai JL, Wu S, Burnstein KL . 1999 Mol. Endocrinol. 13: 1896–1911

  • Hart M, Concordet JP, Lassot I, Albert I, del los SR, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R, Polakis P . 1999 Curr. Biol. 9: 207–210

  • Hayes SA, Zarnegar M, Sharma M, Yang F, Peehl DM, ten Dijke P, Sun Z . 2001 Cancer Res. 61: 2112–2118

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW . 1998 Science 281: 1509–1512

  • Hecht A, Litterst CM, Huber O, Kemler R . 1999 J. Biol. Chem. 274: 18017–18025

  • Heldin CH, Miyazono K, ten Dijke P . 1997 Nature 390: 465–471

  • Hsu W, Shakya R, Costantini F . 2001 J. Cell Biol. 155: 1055–1064

  • Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N, Waterman M, Bowerman B, Clevers H, Shibuya H, Matsumoto K . 1999 Nature 399: 798–802

  • Kerr JF, Searle J . 1973 Virchows Arch. B Cell Pathol. 13: 87–102

  • Kinoshita H, Shi Y, Sandefur C, Meisner LF, Chang C, Choon A, Reznikoff CR, Bova GS, Friedl A, Jarrard DF . 2000 Cancer Res. 60: 3623–3630

  • Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, Brothman AR, Lamb D, Marcelli M, Belldegrun A, Witte ON, Sawyers CL . 1997 Nat. Med. 3: 402–408

  • Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, Clevers H . 1998 Nat. Genet. 19: 379–383

  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H . 1997 Science 275: 1784–1787

  • Kyprianou N, Isaacs JT . 1987 Prostate 11: 41–50

  • Labbe E, Letamendia A, Attisano L . 2000 Proc. Natl. Acad. Sci. USA 97: 8358–8363

  • Lin DL, Whitney MC, Yao Z, Keller ET . 2001 Clin. Cancer Res. 7: 1773–1781

  • Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T . 2001 Cancer Res. 61: 3550–3555

  • Luke MC, Coffey DS . 1994 J. Androl. 15: 41–51

  • Luo J, Duggan DJ, Chen Y, Sauvageot J, Ewing CM, Bittner ML, Trent JM, Isaacs WB . 2001 Cancer Res. 61: 4683–4688

  • McDonald S, Brive L, Agus DB, Scher HI, Ely KR . 2000 Cancer Res. 60: 2317–2322

  • Miller JR, Moon RT . 1996 Genes Dev. 10: 2527–2539

  • Miyazawa K, Iwaya K, Kuroda M, Harada M, Serizawa H, Koyanagi Y, Sato Y, Mizokami Y, Matsuoka T, Mukai K . 2000 Virchows Arch. 437: 508–513

  • Morin PJ . 1999 Bioessays 21: 1021–1030

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW . 1997 Science 275: 1787–1790

  • Muller T, Choidas A, Reichmann E, Ullrich A . 1999 J. Biol. Chem. 274: 10173–10183

  • Nishita M, Hashimoto MK, Ogata S, Laurent MN, Ueno N, Shibuya H, Cho KW . 2000 Nature 403: 781–785

  • Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW . 1997 J. Biol. Chem. 272: 24735–24738

  • Orford K, Orford CC, Byers SW . 1999 J. Cell Biol. 146: 855–868

  • Palmer HG, Gonzalez-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M, Munoz A . 2001 J. Cell Biol. 154: 369–387

  • Park WS, Oh RR, Park JY, Lee SH, Shin MS, Kim YS, Kim SY, Lee HK, Kim PJ, Oh ST, Yoo NJ, Lee JY . 1999 Cancer Res. 59: 4257–4260

  • Planz B, Wang Q, Kirley SD, Lin CW, McDougal WS . 1998 J. Urol. 160: 1850–1855

  • Playford MP, Bicknell D, Bodmer WF, Macaulay VM . 2000 Proc. Natl. Acad. Sci. USA 97: 12103–12108

  • Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER . 1999 Am. J. Pathol. 154: 325–329

  • Roose J, Clevers H . 1999 Biochim. Biophys. Acta 1424: M23–M37

  • Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA . 2000 Science 289: 950–953

  • Sachdev S, Bruhn L, Sieber H, Pichler A, Melchior F, Grosschedl R . 2001 Genes Dev. 15: 3088–3103

  • Sadar MD . 1999 J. Biol. Chem. 274: 7777–7783

  • Sadot E, Simcha I, Shtutman M, Ben Ze'ev A, Geiger B . 1998 Proc. Natl. Acad. Sci. USA 95: 15339–15344

  • Sambrook J, Fritsch EF, Maniatis T . 1989 Molecular Cloning: a Laboratory Manual Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY

    Google Scholar 

  • Sandford NL, Searle JW, Kerr JF . 1984 Pathology 16: 406–410

  • Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokina T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y . 2000 Nat. Genet. 24: 245–250

  • Shih IM, Yu J, He TC, Vogelstein B, Kinzler KW . 2000 Cancer Res. 60: 1671–1676

  • Takeichi M . 1991 Science 251: 1451–1455

  • Takemaru KI, Moon RT . 2000 J. Cell Biol. 149: 249–254

  • Tetsu O, McCormick F . 1999 Nature 398: 422–426

  • Tindall DJ, Scardino PT . 1999 Prostate 38: 166–171

  • Truica CI, Byers S, Gelmann EP . 2000 Cancer Res. 60: 4709–4713

  • Umbas R, Schalken JA, Aalders TW, Carter BS, Karthaus HF, Schaafsma HE, Debruyne FM, Isaacs WB . 1992 Cancer Res. 52: 5104–5109

  • van Bokhoven A, Varella-Garcia M, Korch C, Miller GJ . 2001 Cancer Res. 61: 6340–6344

  • Voeller HJ, Truica CI, Gelmann EP . 1998 Cancer Res. 58: 2520–2523

  • Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan D, Hung MC . 2000 Cancer Res. 60: 6841–6845

  • Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL . 1998 Proc. Natl. Acad. Sci. USA 95: 15587–15591

  • Yanagisawa J, Yanagi Y, Masuhiro Y, Suzawa M, Watanabe M, Kashiwagi K, Toriyabe T, Kawabata M, Miyazono K, Kato S . 1999 Science 283: 1317–1321

  • Yost C, Farr III GH, Pierce SB, Ferkey DM, Chen MM, Kimelman D . 1998 Cell 93: 1031–1041

  • Yuan H, Mao J, Li L, Wu D . 1999 J. Biol. Chem. 274: 30419–30423

  • Zhu AJ, Watt FM . 1999 Development 126: 2285–2298

  • Zorn AM, Barish GD, Williams BO, Lavender P, Klymkowsky MW, Varmus HE . 1999 Mol. Cell 4: 487–498

Download references

Acknowledgements

This study was supported by SPORE grant CA58236 from the National Cancer Institute. We thank Dr John Isaacs (JHU), Dr Ken Kinzler (JHU), Dr Ron Rodriguez (JHU), and Dr Charles Sawyers (UCLA) for supplying reagents used in this study.

Author information

Authors and Affiliations

  1. Brady Urological Institute Research Laboratories, The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, MD, USA

    Dennis R Chesire, Charles M Ewing & William B Isaacs

  2. Johns Hopkins Oncology Center, The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, MD, USA

    Wesley R Gage & William B Isaacs

Authors
  1. Dennis R Chesire
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles M Ewing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wesley R Gage
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William B Isaacs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William B Isaacs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chesire, D., Ewing, C., Gage, W. et al. In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis. Oncogene 21, 2679–2694 (2002). https://doi.org/10.1038/sj.onc.1205352

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205352

Keywords

This article is cited by

Search

Advanced search

Quick links