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 journalArticlepeer-review

393 Scopus citations


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 languageEnglish (US)
Pages (from-to)454-458
Number of pages5
JournalNature genetics
Issue number5
StatePublished - May 2010
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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