The retinoblastoma (Rb) tumor suppressor controls cellular proliferation, survival, and differentiation and is functionally inactivated by mutations or hyperphosphorylation in most human cancers. Although activation of endogenous Rb is thought to provide an effective approach to suppress cell proliferation, long-term inhibition of apoptosis by active Rb may have detrimental consequences in vivo. To directly test these paradigms, we targeted phosphorylation-resistant constitutively active Rb alleles, RbΔKs, to the mouse mammary gland. Pubescent transgenic females displayed reduced ductal elongation and cell proliferation at the endbuds. Postpuberty transgenic mice exhibited precocious cellular differentiation and β-casein expression and extended survival of the mammary epithelium with a moderate but specific effect on the expression of E2F1, IGF1Rα, and phospho–protein kinase B/AKT. Remarkably, ∼30% RbΔK transgenic females developed focal hyperplastic nodules, and ∼7% exhibited full-blown mammary adenocarcinomas within 15 mo. Expression of the RbΔK transgene in these mammary tumors was reduced greatly. Our results suggest that transient activation of Rb induces cancer by extending cell survival and that the dual effects of Rb on cell proliferation and apoptosis impose an inherent caveat to the use of the Rb pathway for long-term cancer therapy.
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7 January 2002
Article|
January 03 2002
Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma
Zhe Jiang,
Zhe Jiang
Department of Medicine, Department of Laboratory Medicine and Pathobiology, and Department of Medical Biophysics, University of Toronto, Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, Toronto, Ontario, Canada M5G 2M1
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Eldad Zacksenhaus
Eldad Zacksenhaus
Department of Medicine, Department of Laboratory Medicine and Pathobiology, and Department of Medical Biophysics, University of Toronto, Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, Toronto, Ontario, Canada M5G 2M1
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Zhe Jiang
Department of Medicine, Department of Laboratory Medicine and Pathobiology, and Department of Medical Biophysics, University of Toronto, Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, Toronto, Ontario, Canada M5G 2M1
Eldad Zacksenhaus
Department of Medicine, Department of Laboratory Medicine and Pathobiology, and Department of Medical Biophysics, University of Toronto, Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, Toronto, Ontario, Canada M5G 2M1
Address correspondence to Eldad Zacksenhaus, Div. of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, 67 College St., Rm. 407, Toronto, Ontario, Canada M5G 2M1. Tel.: (416) 340-4800 ex. 5106. Fax: (416) 340-3453. E-mail: [email protected]
*
Abbreviations used in this paper: Cdk, cyclin-dependent kinase; H-E, hematoxylin and eosin; IHC, immunohistochemistry; MMTV, mouse mammary tumor virus; PCNA, proliferation cell nuclear antigen; PKB, protein kinase B; Rb, retinoblastoma; RT, reverse transcribed; TEB, terminal endbud; TUNEL, TdT-mediated dUtp-biotin nick end labeling; WAP, whey acidic protein.
Received:
June 15 2001
Revision Received:
November 15 2001
Accepted:
November 15 2001
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2002
J Cell Biol (2002) 156 (1): 185–198.
Article history
Received:
June 15 2001
Revision Received:
November 15 2001
Accepted:
November 15 2001
Citation
Zhe Jiang, Eldad Zacksenhaus; Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma . J Cell Biol 7 January 2002; 156 (1): 185–198. doi: https://doi.org/10.1083/jcb.200106084
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