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

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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.

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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

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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.

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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

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  1. Priscilla A Furth
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  2. Ud Bar-Peled
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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

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

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