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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Friend, S.H. Alfred Knudson: the importance of a visionary who enables scientists. Genes Chromosom. Cancer 38, 326–328 (2003).
Trotman, L.C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003).
Yan, H. et al. Small changes in expression affect predisposition to tumorigenesis. Nat. Genet. 30, 25–26 (2002).
Salmena, L., Carracedo, A. & Pandolfi, P.P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).
Knudson, A.G. Two genetic hits (more or less) to cancer. Nat. Rev. Cancer 1, 157–162 (2001).
Knudson, A.G. Hereditary cancer: two hits revisited. J. Cancer Res. Clin. Oncol. 122, 135–140 (1996).
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).
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).
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).
Di Cristofano, A. & Pandolfi, P.P. The multiple roles of PTEN in tumor suppression. Cell 100, 387–390 (2000).
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).
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).
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).
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).
Di Cristofano, A. et al. Impaired Fas response and autoimmunity in Pten+/− mice. Science 285, 2122–2125 (1999).
Hong, F. et al. RankProd: a bioconductor package for detecting differentially expressed genes in meta-analysis. Bioinformatics 22, 2825–2827 (2006).
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).
Bose, S. et al. Reduced expression of PTEN correlates with breast cancer progression. Hum. Pathol. 33, 405–409 (2002).
Richardson, A.L. et al. X-chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9, 121–132 (2006).
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).
Trotman, L.C. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523–527 (2006).
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
Authors and Affiliations
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
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8 and Supplementary Table 1 (PDF 5636 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.556
This article is cited by
-
RNA m6A methylation and regulatory proteins in pulmonary arterial hypertension
Hypertension Research (2024)
-
Pan-cancer genomic analysis shows hemizygous PTEN loss tumors are associated with immune evasion and poor outcome
Scientific Reports (2023)
-
Targeting the E3 ligase NEDD4 as a novel therapeutic strategy for IGF1 signal pathway-driven gastric cancer
Oncogene (2023)
-
Hyperphosphorylated PTEN exerts oncogenic properties
Nature Communications (2023)
-
Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression
Cellular and Molecular Life Sciences (2023)