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 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. 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.