Journal Article

Subtle variations in Pten dose determine cancer susceptibility

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

2010

Overview

Pier Paolo Pandolfi and colleagues report the generation of mice that express 80% of normal levels of the PTEN tumor suppressor. The mice develop a spectrum of tumors, including breast tumors that retain two copies of Pten , suggesting that subtle changes in expression can predispose to tumorigenesis. 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 development 2 , 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 syndromes 4 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/726/649 / 631/208/727/2000 / 631/67/1347 / 631/67/69 / Agriculture / Analysis / Animal Genetics and Genomics / Animals / Autoimmune diseases / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Breast Neoplasms - genetics / Cancer / Cancer Research / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Disease susceptibility / Female / Females / Fundamental and applied biological sciences. Psychology / Gene Dosage / Gene Expression Regulation, Neoplastic / Gene Function / Gene mutations / Genes, Tumor Suppressor / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Heterozygote / Homozygote / Human Genetics / Humans / letter / Male / Mammary Neoplasms, Animal - genetics / Mice / Mice, Transgenic / Models, Genetic / Molecular and cellular biology / Mutation / Proteins / PTEN Phosphohydrolase - genetics / Rodents / Tumors