Subtle variations in Pten dose determine cancer susceptibility

Andrea Alimonti; Arkaitz Carracedo; John G. Clohessy; Lloyd C. Trotman; Caterina Nardella; Ainara Egia; Leonardo Salmena; Katia Sampieri; William J. Haveman; Edi Brogi; Andrea L. Richardson; Jiangwen Zhang; Pier Paolo Pandolfi

doi:10.1038/ng.556

Subtle variations in Pten dose determine cancer susceptibility

Andrea Alimonti, Arkaitz Carracedo, John G. Clohessy, Lloyd C. Trotman, Caterina Nardella, Ainara Egia, Leonardo Salmena, Katia Sampieri, William J. Haveman, Edi Brogi, Andrea L. Richardson, Jiangwen Zhang, Pier Paolo Pandolfi

Research output: Contribution to journal › Article › peer-review

393 Scopus citations

Abstract

Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG). It has been hypothesized that subtle variations in TSG expression can promote cancer development. 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 syndromes. Here we analyze Pten hypermorphic mice (Pten hy/+), expressing 80% normal levels of Pten. Pten hy/+ 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.

Original language	English (US)
Pages (from-to)	454-458
Number of pages	5
Journal	Nature genetics
Volume	42
Issue number	5
DOIs	https://doi.org/10.1038/ng.556
State	Published - May 2010
Externally published	Yes

ASJC Scopus subject areas

Genetics

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@article{42cf1fb3b65b4b388262ec327a31e53c,

title = "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). It has been hypothesized that subtle variations in TSG expression can promote cancer development. 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 syndromes. Here we analyze Pten hypermorphic mice (Pten hy/+), expressing 80% normal levels of Pten. Pten hy/+ 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.",

author = "Andrea Alimonti and Arkaitz Carracedo and Clohessy, {John G.} and Trotman, {Lloyd C.} and Caterina Nardella and Ainara Egia and Leonardo Salmena and Katia Sampieri and Haveman, {William J.} and Edi Brogi and Richardson, {Andrea L.} and Jiangwen Zhang and Pandolfi, {Pier Paolo}",

note = "Funding Information: 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.",

year = "2010",

month = may,

doi = "10.1038/ng.556",

language = "English (US)",

volume = "42",

pages = "454--458",

journal = "Nature genetics",

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T1 - Subtle variations in Pten dose determine cancer susceptibility

AU - Alimonti, Andrea

AU - Carracedo, Arkaitz

AU - Clohessy, John G.

AU - Trotman, Lloyd C.

AU - Nardella, Caterina

AU - Egia, Ainara

AU - Salmena, Leonardo

AU - Sampieri, Katia

AU - Haveman, William J.

AU - Brogi, Edi

AU - Richardson, Andrea L.

AU - Zhang, Jiangwen

AU - Pandolfi, Pier Paolo

N1 - Funding Information: 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.

PY - 2010/5

Y1 - 2010/5

N2 - Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG). It has been hypothesized that subtle variations in TSG expression can promote cancer development. 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 syndromes. Here we analyze Pten hypermorphic mice (Pten hy/+), expressing 80% normal levels of Pten. Pten hy/+ 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.

AB - Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG). It has been hypothesized that subtle variations in TSG expression can promote cancer development. 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 syndromes. Here we analyze Pten hypermorphic mice (Pten hy/+), expressing 80% normal levels of Pten. Pten hy/+ 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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Subtle variations in Pten dose determine cancer susceptibility

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