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Subtle variations in Pten dose determine cancer susceptibility


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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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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Authors and Affiliations



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.

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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).

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