Subtle variations in Pten dose determine cancer susceptibility Journal Article
| Authors: | 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. |
| Article 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. © 2010 Nature America, Inc. All rights reserved. |
| Keywords: | controlled study; gene mutation; mutation; nonhuman; cell proliferation; animal cell; mouse; animals; mice; mus; cancer susceptibility; genetic predisposition to disease; breast cancer; gene expression; gene expression profiling; animal experiment; animal model; lung cancer; breast neoplasms; heterozygote; carcinogenesis; mice, transgenic; tumor suppressor gene; gene expression regulation, neoplastic; heterozygosity; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; homozygote; models, genetic; gene dosage; pheochromocytoma; uterus cancer; lymphadenopathy; genes, tumor suppressor; penetrance; intestine polyp; pten gene; mammary neoplasms, animal |
| Journal Title: | Nature Genetics |
| Volume: | 42 |
| Issue: | 5 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-05-01 |
| Start Page: | 454 |
| End Page: | 458 |
| Language: | English |
| DOI: | 10.1038/ng.556 |
| PUBMED: | 20400965 |
| PROVIDER: | scopus |
| PMCID: | PMC3118559 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 18" - "Export Date: 20 April 2011" - "CODEN: NGENE" - "Source: Scopus" |
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