Subtle variations in Pten dose determine cancer susceptibility

Alimonti, A., Carracedo, A., Clohessy, J. G., Trotman, L. C., Nardella, C., Egia, A., Salmena, L., Sampieri, K., Haveman, W. J., Brogi, E., Richardson, A. L., Zhang, J., Pandolfi, P. P. (May 2010) Subtle variations in Pten dose determine cancer susceptibility. Nature Genetics, 42 (5). pp. 454-458. ISSN 10614036 (ISSN) (In Press)

URL: http://www.ncbi.nlm.nih.gov/pubmed/20400965
DOI: 10.1038/ng.556

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<sup>hy/+</sup>), expressing 80% normal levels of Pten. Pten<sup>hy/+</sup> 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.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > breast cancer
organism description > animal > mammal > rodent > mouse
CSHL Authors:
Communities: CSHL labs > Trotman lab
Depositing User: CSHL Librarian
Date: May 2010
Date Deposited: 23 Sep 2011 19:53
Last Modified: 08 May 2013 16:52
PMCID: PMC3118559
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15346

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