PTEN deficiency is fully penetrant for prostate adenocarcinoma in C57BL/6 mice via mTOR-dependent growth

Jorge Blando, Melisa Portis, Fernando Benavides, Angela Alexander, Gordon Mills, Bhuvanesh Dave, Claudio J. Conti, Jeri Kim, Cheryl Lyn Walker

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The tumor suppressor phosphatase and tensin homolog (PTEN) is frequently involved in human prostate carcinoma. PTEN is therefore an attractive target for the development of preclinical animal models. Prostate intraepithelial neoplasia lesions develop in mice with Pten heterozygosity, but disease progression has been reported only in combination with either other tumor suppressor gene alterations or the conditional inactivation of both Pten alleles in prostate epithelial cells. We report that on a C57BL/6 background, in contrast to previous studies on mixed 129 genetic backgrounds, Pten locus heterozygosity is fully penetrant for the development of prostate adenocarcinoma. Grossly observable tumors were detected at 6 months of age, and, by 10 to 12 months, 100% of examined mice developed adenocarcinoma of the anterior prostate. Furthermore, double heterozygotes carrying both Pten and Tsc2-null alleles showed no increase relative to Pten+/- heterozygotes in either lesion development or progression. Lesions in both Pten+/-; Tsc2+/-, and Pten+/- mice exhibited loss of PTEN expression and activation of PI3K signaling. PI3K activation occurred early in prostate intraepithelial neoplasia lesion formation in these animals, consistent with loss of PTEN function, and contributed to the etiology of tumors that developed in Pten+/- mice. Furthermore, prostate lesion growth in Pten+/- mice was dependent on mTOR, as evidenced by a reduction in both phospho-S6 levels and proliferative index after rapamycin treatment.

Original languageEnglish (US)
Pages (from-to)1869-1879
Number of pages11
JournalAmerican Journal of Pathology
Volume174
Issue number5
DOIs
StatePublished - May 2009
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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