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Subtle variations in Pten dose determine cancer susceptibility

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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Figure 1: A subtle reduction in the dose of Pten dictates overall survival in Ptenhy/+ mice and initiates mammary tumorigenesis.
Figure 2: A subtle variation of Pten gene expression promotes hyper proliferation in a tissue-specific manner.
Figure 3
Figure 4: Gene expression profiles of Ptenhy/+ MEFs, MMECs and human breast cancer samples with reduced PTEN levels.
Figure 5: Implications for tumorigenesis upon subtle reduction of TSG levels.

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References

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

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  4. Salmena, L., Carracedo, A. & Pandolfi, P.P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  7. Ma, L. 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).

    CAS  Article  Google Scholar 

  8. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P.P. Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19, 348–355 (1998).

    CAS  Article  Google Scholar 

  9. Venkatachalam, S. 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).

    CAS  Article  Google Scholar 

  10. Di Cristofano, A. & Pandolfi, P.P. The multiple roles of PTEN in tumor suppression. Cell 100, 387–390 (2000).

    CAS  Article  Google Scholar 

  11. Suzuki, A. 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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  14. McDevitt, M.A., Shivdasani, R.A., Fujiwara, Y., Yang, H. & Orkin, S.H.A. “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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  17. Saal, L.H. 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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

Download references

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.

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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.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

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The authors declare no competing financial interests.

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Alimonti, A., Carracedo, A., Clohessy, J. et al. Subtle variations in Pten dose determine cancer susceptibility. Nat Genet 42, 454–458 (2010). https://doi.org/10.1038/ng.556

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