Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten

Stéphanie A. Backman, Danny Ghazarian, Kelvin So, Otto Sanchez, Kay Uwe Wagner, Lothar Hennighausen, Akira Suzuki, Ming Sound Tsao, William B. Chapman, Vuk Stambolic, Tak W. Mak

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Abstract

PTEN is a tumor suppressor gene mutated in various advanced human neoplasias, including glioblastomas and prostate, breast, endometrial, and kidney cancers. This tumor suppressor is a lipid phosphatase that negatively regulates cell survival and proliferation mediated by phosphatidylinositol 3-kinase/protein kinase B signaling. Using the Cre-loxP system, we selectively inactivated Pten in murine tissues in which the MMTV-LTR promoter is active, resulting in hyperproliferation and neoplastic changes in Pten-null skin and prostate. These phenotypes had early onset and were completely penetrant. Abnormalities in Pten mutant skin consisted of mild epidermal hyperplasia, whereas prostates from these mice exhibited high-grade prostatic intraepithelial neoplasia (HGPIN) that frequently progressed to focally invasive cancer. These data demonstrate that Pten is an important physiological regulator of growth in the skin and prostate. Further, the early onset of HGPIN in Pten mutant males is unique to this animal model and implicates PTEN mutations in the initiation of prostate cancer. Consistent with high PTEN mutation rates in human prostate tumors, these data indicate that PTEN is a critical tumor suppressor in this organ.

Original languageEnglish (US)
Pages (from-to)1725-1730
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number6
DOIs
StatePublished - Feb 10 2004

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Backman, S. A., Ghazarian, D., So, K., Sanchez, O., Wagner, K. U., Hennighausen, L., Suzuki, A., Tsao, M. S., Chapman, W. B., Stambolic, V., & Mak, T. W. (2004). Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten. Proceedings of the National Academy of Sciences of the United States of America, 101(6), 1725-1730. https://doi.org/10.1073/pnas.0308217100