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.
authors.affiliation: Cancer Genetics Program, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Alimonti
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: John G
authors.initials: JG
authors.lastname: Clohessy
authors.forename: Lloyd C
authors.initials: LC
authors.lastname: Trotman
authors.forename: Caterina
authors.initials: C
authors.lastname: Nardella
authors.forename: Ainara
authors.initials: A
authors.lastname: Egia
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: Katia
authors.initials: K
authors.lastname: Sampieri
authors.forename: William J
authors.initials: WJ
authors.lastname: Haveman
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse
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