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Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse

Nature Genetics volume 27, pages 222–224 (2001)Cite this article

Abstract

The genetic bases underlying prostate tumorigenesis are poorly understood. Inactivation of the tumor-suppressor gene PTEN and lack of p27KIP1 expression have been detected in most advanced prostate cancers1,2. But mice deficient for Cdkn1b (encoding p27Kip1) do not develop prostate cancer3,4,5. PTEN activity leads to the induction of p27KIP1 expression, which in turn can negatively regulate the transition through the cell cycle6. Thus, the inactivation of p27KIP1 may be epistatic to PTEN in the control of the cell cycle. Here we show that the concomitant inactivation of one Pten allele and one or both Cdkn1b alleles accelerates spontaneous neoplastic transformation and incidence of tumors of various histological origins. Cell proliferation, but not cell survival, is increased in Pten+/−/Cdkn1b−/− mice. Moreover, Pten+/−/Cdkn1b−/− mice develop prostate carcinoma at complete penetrance within three months from birth. These cancers recapitulate the natural history and pathological features of human prostate cancer. Our findings reveal the crucial relevance of the combined tumor-suppressive activity of Pten and p27Kip1 through the control of cell-cycle progression.

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Figure 1: Pten+/− mice are highly susceptible to developing epithelial tumors.
Figure 2: Reduction of the Cdkn1b gene dose accelerates tumorigenesis in Pten+/− mice.
Figure 3: Prostate tumorigenesis in Pten+/−/Cdkn1b−/− mice.
Figure 4: Increased proliferation of prostate epithelial cells in Pten+/−/Cdkn1b−/− mice.

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Acknowledgements

We thank C. Abate-Shen, M. Shen, P. Scardino and H.I. Scher for advice and discussions; M. Jiao for the preparation of pathological samples; and S. Kim for critical suggestions concerning the Pten immunohistochemical analysis. P.P.P. is a Scholar of the Leukemia & Lymphoma Society of America (formerly known as the Leukemia Society of America). This work was supported by the NCI and by the I.T. Hirschl/M. Weill-Caulier Foundation to P.P.P.

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Authors and Affiliations

  1. Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, New York, USA

    Antonio Di Cristofano, Marika De Acetis & Pier P Pandolfi

  2. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, New York, USA

    Antonio Di Cristofano, Marika De Acetis, Andrew Koff & Pier P Pandolfi

  3. Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, New York, USA

    Carlos Cordon-Cardo

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  1. Antonio Di Cristofano
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  2. Marika De Acetis
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  4. Carlos Cordon-Cardo
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  5. Pier P Pandolfi
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Correspondence to Pier P Pandolfi.

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Di Cristofano, A., De Acetis, M., Koff, A. et al. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 27, 222–224 (2001). https://doi.org/10.1038/84879

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