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:

Loss of anti-mitotic effects of Bcl-2 with retention of anti-apoptotic activity during tumor progression in a mouse model

Oncogene volume 18, pages 6589–6596 (1999)Cite this article

Abstract

Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in several different human cancers including breast. Gain of Bcl-2 function in mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model of breast cancer progression to determine its effect on epithelial cell survival and proliferation at three key stages in oncogenesis: the initial proliferative process, hyperplasia, and cancer. During the initial proliferative process, Bcl-2 strongly inhibited both apoptosis and mitotic activity. However as tumorigenesis progressed to hyperplasia and adenocarcinoma, the inhibitory effects on mitotic activity were lost. In contrast, anti-apoptotic activity persisted in both hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate during cancer progression. In this model, retention of anti-apoptotic activity with loss of anti-proliferative action resulted in earlier tumor presentation.

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 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Abbreviations

WAP:

whey acidic protein

TAg:

Simian virus 40 large T antigen

WAP-TAg:

a transgenic mouse model of breast cancer progression in which TAg expression is targeted to mammary epithelial cells using the WAP promoter

DMBA:

dimethylbenz(a)anthracene

H&E:

hematoxylin and eosin

HPF:

high power fields

s.e.m.:

standard error of the mean

References

  • Adams JM and Cory S. . 1998 Science 281: 1322–1326.

  • Basola F, Fiore L, Ciardiello F, Calvo S, Fontanini G, Conaldi PG and Toniolo A. . 1994 Int. J. Cancer 56: 736–742.

  • Bonetti A, Zaninelli M, Leone R, Cetto GL, Pelosi G, Biolo S, Menghi A, Manfrin E, Bonetti F and Piubello Q. . 1998 Clin. Cancer Res. 4: 2331–2336.

  • Borner C. . 1996 J. Biol. Chem. 271: 12695–12698.

  • Bottinger EP, Jakubczak JL, Haines DC, Bagnall K and Wakefield LM. . 1997 Cancer Res. 57: 5564–5570.

  • Castano E, Kleyner Y and Dynlacht BD. . 1998 Mol. Cell. Biol. 18: 5380–5391.

  • Coats S, Whyte P, Fero ML, Lacy S, Chung G, Randel E, Firpo E and Roberts JM. . 1999 Curr. Biol. 9: 163–173.

  • De Luca A, MacLachlan TK, Bagella L, Dean C, Howard CM, Claudio PP, Baldi A, Khalili K and Giodano A. . 1997 J. Biol. Chem. 272: 20971–20974.

  • Demeril D, Laucirica R, Fishman A, Owens RG, Grey MM, Kaplan AL and Ramzy I. . 1996 Cancer 77: 1494–1500.

  • Franch HA, Shay JW, Alpern RJ and Preisig PA. . 1995 J. Cell. Biol. 129: 245–254.

  • Frankfurt OS, Robb JA, Sugarbaker EV and Villa L. . 1997 Clin. Cancer Res. 3: 465–471.

  • Gasparini G, Barbareschi M, Doglioni C, Palma PD, Mauri FA, Boracchi P, Bevilacqua P, Caffo O, Morelli L and Verderio P. . 1995 Clin. Cancer Res. 1: 189–198.

  • Gil-Gomez G, Berns A and Brady HJ. . 1998 EMBO J. 17: 7209–7218.

  • Hakem A, Sasaki T, Kozieradzki I and Penninger JM. . 1999 J. Exp. Med. 189: 957–968.

  • Huang DC, O'Reilly LA, Strasser A and Cory S. . 1997 EMBO J. 16: 4628–4638.

  • Jäger R, Herzer U, Schenkel J and Weiher H. . 1997 Oncogene 15: 1787–1795.

  • Jerry DJ, Butel JS, Donehower LA, Paulson EJ, Cochran C, Wiseman RW and Medina D. . 1994 Mol. Carcinog. 9: 175–183.

  • Kitada S, Krajewska M, Zhang X, Scudiero D, Zapata JM, Wang HG, Shabaik A, Tudor G Krajewski S, Myers TG, Johnson GS, Sausville EA and Reed JC. . 1998 Am. J. Pathol. 152: 51–61.

  • Korsmeyer SJ. . 1992 Blood 80: 879–886.

  • Li M, Hu J, Heermeier K, Hennighausen L and Furth PA. . 1996a Cell Growth Diff. 7: 13–20.

  • Li M, Hu J, Heermeier K, Hennighausen L and Furth PA. . 1996b Cell Growth Diff. 7: 3–11.

  • Lind EF, Wayne J, Wang QZ, Staeva T, Stolzer A and Petrie HT. . 1999 J. Immunol. 162: 5374–5379.

  • Linette GP, Li Y, Roth K and Korsmeyer SJ. . 1996 Proc. Natl. Acad. Sci. USA 93: 9545–9552.

  • Meikrantz W, Gisselbrecht S, Tam SW and Schlegel R. . 1994 Proc. Natl. Acad. Sci. USA 91: 3754–3758.

  • Meikrantz W and Schlegel R. . 1996 J. Biol. Chem. 271: 10205–10209.

  • Moses HL. . 1992 Mol. Reprod. Dev. 32: 179–184.

  • O'Reilly LA, Harris AW and Strasser A. . 1997a Int. Immunol. 9: 1291–1301.

  • O'Reilly LA, Harris AW, Tarlinton DM, Corcoran LM and Strasser A. . 1997b J. Immunol. 159: 2301–2311.

  • Pierce Jr DF, Gorska AE, Chytil A, Meise KS, Page DL, Coffey Jr RJ and Moses HL. . 1995 Proc. Natl. Acad. Sci. USA 92: 4254–4258.

  • Pietenpol JA, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW and Vogelstein B. . 1994 Cancer Res. 54: 3714–3717.

  • Pillai MR, Halabi S, McKalip A, Jayaprakash PG, Rajalekshmi TN, Nair MK and Herman B. . 1996 Cancer Epidemiol. Biomarkers Prev. 5: 329–335.

  • Ravaiolo A, Bagli L, Zucchini A and Monti F. . 1998 Cell. Prolif. 31: 113–126.

  • Saegusa M, Takano Y, Hashimura M, Shoji Y and Okayasu I. . 1995 Cancer 76: 2297–2303.

  • Schorr K, Li M, Bar-Peled U, Lewis A, Heredia A, Lewis B, Knudson CM, Korsmeyer SJ, Jäger R, Weiher H and Furth PA. . 1999a Cancer Res. 59: 2541–2545.

  • Schorr K, Li M, Krajewski S, Reed JC and Furth PA. . 1999b J. Mamm. Gland Biol. Neoplasia 4: 153–164.

  • Schwarz JK, Bassing CH, Kovesdi I, Datto MB, Blazing M, George S, Wang X-F and Nevins JR. . 1995 Proc. Natl. Acad. Sci. USA 92: 483–487.

  • Shankey TV, Rabinovitch PS, Bagwell B, Bauer KD, Duque RE and Hedley DW. . 1993 Cytometry 14: 472–477.

  • Shiyanov P, Bagchi S, Adami G, Kokontis J, Hay N, Arroyo M, Morozov A and Raychaudhuri P. . 1996 Mol. Cell. Biol. 16: 737–744.

  • Sierra A, Castellsague X, Tortola S, Escobedo A, Lloveras B, Peinado MA, Moreno A and Fabra A. . 1996 Clin. Cancer Res. 2: 1887–1894.

  • Strom DK, Cleveland JL, Chellappan S, Nip J and Hiebert SW. . 1998 Cell Growth Differ. 9: 59–69.

  • Theodorakis P, D'Sa-Eipper C, Subramanian T and Chinnadurai G. . 1996 Oncogene 12: 1707–1713.

  • Tsujimoto Y, Finger LR, Yunis J, Nowell PC and Croce CM. . 1984 Science 226: 1097–1099.

  • Tzeng Y-J, Guhl E, Graessmann M and Graessmann A. . 1993 Oncogene 8: 1965–1971.

  • Uhlmann EJ, D'Sa-Eipper C, Subramanian T, Wagner AJ, Hay N and Chinnadurai G. . 1996 Cancer Res. 56: 2506–2509.

  • Vindelov LL, Christensen IJ and Nissen NI. . 1983 Cytometry 3: 323–327.

  • Zalvide J, Stubdal H and DeCaprio JA. . 1998 Mol. Cell. Biol. 18: 1408–1415.

  • Zapata JM, Krajewska M, Krajewski S, Huang RP, Takayama S, Wang HG, Adamson E and Reed JC. . 1998 Breast Cancer Res. Treat. 47: 129–140.

  • Zhang GJ, Kimijima I, Tsuchiya A and Abe R. . 1998 Oncol. Rep. 5: 1211–1216.

Download references

Acknowledgements

Supported by National Cancer Institute grant CA-68033 (to PA Furth) and the Veterans Administration Research Service (PA Furth and R Russell). U Bar-Peled was supported in part by a BARD fellowship.

Author information

Authors and Affiliations

  1. Division of Infectious Disease, Department of Medicine, Institute of Human Virology, University of Maryland Medical School, Baltimore, 21201, Maryland, MD, USA

    Priscilla A Furth, Ud Bar-Peled, Minglin Li & Albert Lewis

  2. The Baltimore Veterans Affairs Medical Center, Baltimore, 21201, Maryland, MD, USA

    Priscilla A Furth, Ud Bar-Peled, Minglin Li, Albert Lewis & Robert G Russell

  3. Department of Physiology, University of Maryland Medical School, Baltimore, 21201, Maryland, MD, USA

    Priscilla A Furth

  4. Baylor College of Medicine and Methodist Hospital, Houston, 77030, Texas, TX, USA

    Rodolfo Laucirica

  5. Forschungszentrum Karlsruhe, Institut für Genetik, D-76021, Karlsruhe, Germany

    Richard Jäger

  6. Institut für Diabetesforschung, Kölner Platz 1, 80804, München, Germany

    Hans Weiher

Authors
  1. Priscilla A Furth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ud Bar-Peled
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Minglin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Albert Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rodolfo Laucirica
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard Jäger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hans Weiher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert G Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Furth, P., Bar-Peled, U., Li, M. et al. Loss of anti-mitotic effects of Bcl-2 with retention of anti-apoptotic activity during tumor progression in a mouse model. Oncogene 18, 6589–6596 (1999). https://doi.org/10.1038/sj.onc.1203073

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203073

Keywords

This article is cited by

Search

Advanced search

Quick links