Letter | Published:

Subtle variations in Pten dose determine cancer susceptibility

Nature Genetics 42, 454–458 (2010) | Download Citation

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Abstract

Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG)1. It has been hypothesized that subtle variations in TSG expression can promote cancer development2,3. However, this hypothesis has not yet been definitively supported in vivo. Pten is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes4. Here we analyze Pten hypermorphic mice (Ptenhy/+), expressing 80% normal levels of Pten. Ptenhy/+ mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosity. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner.

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References

  1. 1.

    Alfred Knudson: the importance of a visionary who enables scientists. Genes Chromosom. Cancer 38, 326–328 (2003).

  2. 2.

    et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003).

  3. 3.

    et al. Small changes in expression affect predisposition to tumorigenesis. Nat. Genet. 30, 25–26 (2002).

  4. 4.

    , & Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).

  5. 5.

    Two genetic hits (more or less) to cancer. Nat. Rev. Cancer 1, 157–162 (2001).

  6. 6.

    Hereditary cancer: two hits revisited. J. Cancer Res. Clin. Oncol. 122, 135–140 (1996).

  7. 7.

    et al. Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression. Genes Dev. 19, 1779–1786 (2005).

  8. 8.

    , , & Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19, 348–355 (1998).

  9. 9.

    et al. Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J. 17, 4657–4667 (1998).

  10. 10.

    & The multiple roles of PTEN in tumor suppression. Cell 100, 387–390 (2000).

  11. 11.

    et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 8, 1169–1178 (1998).

  12. 12.

    et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. USA 96, 1563–1568 (1999).

  13. 13.

    et al. HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J. 22, 1134–1146 (2003).

  14. 14.

    , , , & “Knockdown” mutation created by cis-element gene targeting reveals the dependence of erythroid cell maturation on the level of transcription factor GATA-1. Proc. Natl. Acad. Sci. USA 94, 6781–6785 (1997).

  15. 15.

    et al. Impaired Fas response and autoimmunity in Pten+/− mice. Science 285, 2122–2125 (1999).

  16. 16.

    et al. RankProd: a bioconductor package for detecting differentially expressed genes in meta-analysis. Bioinformatics 22, 2825–2827 (2006).

  17. 17.

    et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 65, 2554–2559 (2005).

  18. 18.

    et al. Reduced expression of PTEN correlates with breast cancer progression. Hum. Pathol. 33, 405–409 (2002).

  19. 19.

    et al. X-chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9, 121–132 (2006).

  20. 20.

    et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet. 41, 619–624 (2009).

  21. 21.

    et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523–527 (2006).

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Acknowledgements

We thank Z. Chen for help with genotyping and characterization of the Pten hypomorphic mutant mice. This study was supported, in part, by US National Cancer Institute grants (SPORE 92629 in Prostate Cancer, MMHCC CA-84292 and RO1 CA-82328). A.C. was supported by a long-term European Molecular Biology Organization fellowship.

Author information

    • Lloyd C Trotman

    Current address: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

    • Arkaitz Carracedo
    •  & John G Clohessy

    These authors contributed equally to this work.

Affiliations

  1. Cancer Genetics Program, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Andrea Alimonti
    • , Arkaitz Carracedo
    • , John G Clohessy
    • , Caterina Nardella
    • , Ainara Egia
    • , Leonardo Salmena
    • , Katia Sampieri
    • , William J Haveman
    •  & Pier Paolo Pandolfi

  2. Department of Pathology, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Andrea Alimonti
    • , Arkaitz Carracedo
    • , John G Clohessy
    • , Caterina Nardella
    • , Ainara Egia
    • , Leonardo Salmena
    • , Katia Sampieri
    • , William J Haveman
    •  & Pier Paolo Pandolfi

  3. Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Andrea Alimonti
    • , Arkaitz Carracedo
    • , John G Clohessy
    • , Lloyd C Trotman
    • , Caterina Nardella
    • , Ainara Egia
    • , Leonardo Salmena
    • , William J Haveman
    •  & Pier Paolo Pandolfi

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

    • Andrea Alimonti
    • , Arkaitz Carracedo
    • , John G Clohessy
    • , Caterina Nardella
    • , Ainara Egia
    • , Leonardo Salmena
    • , William J Haveman
    • , Edi Brogi
    •  & Pier Paolo Pandolfi

  5. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Andrea L Richardson

  6. Faculty of Arts and Sciences (FAS), Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Jiangwen Zhang

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Contributions

A.A., L.C.T. and P.P.P. conceived and designed the experiments. A.A., A.C., J.G.C., C.N., A.E., L.S., K.S. and W.J.H. performed the experiments. A.A., A.C., J.G.C., C.N., L.S., E.B., A.L.R., J.Z. and P.P.P. analyzed the data. A.A., A.C., J.G.C. and P.P.P. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

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DOI

https://doi.org/10.1038/ng.556

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