Gata3 antagonizes cancer progression in Pten-deficient prostates

Alana Nguyen, Mathieu Tremblay, Katharina Haigh, Ismael Hervekoumakpayi, Marilene Paquet, Pier Paolo Pandolfi, Anne Marie Mes-Masson, Fred Saad, Jody Haigh, Maxime Bouchard

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

Loss of the tumor suppressor PTEN is a common occurrence in prostate cancer. This aberration leads to the ectopic activation of the PI3K-Akt pathway, which promotes tumor growth. Here, we show that the transcription factor Gata3 is progressively lost in Pten-deficient mouse prostate tumors as a result of both transcriptional down-regulation and increased proteasomal degradation. To determine the significance of this loss, we used conditional loss- and gain-of-function approaches to manipulate Gata3 expression levels in prostate tumors. Our results show that Gata3 inactivation in Pten-deficient prostates accelerates tumor invasion. Conversely, enforced expression of GATA3 in Pten-deficient tissues markedly delays tumor progression. In Pten-deficient prostatic ducts, enforced GATA3 prevented Akt activation, which correlated with the down-regulation of Pik3cg and Pik3c2a mRNAs, encoding respectively class I and II PI3K subunits. Remarkably, the majority of human prostate tumors similarly show loss of active GATA3 as they progress to the aggressive castrate-resistant stage. In addition, GATA3 expression levels in hormone-sensitive tumors holds predictive value for tumor recurrence. Together, these data establish Gata3 as an important regulator of prostate cancer progression.? 2013. Published by Oxford University Press. All rights reserved.
Original languageEnglish
Pages (from-to)2400 - 2410
Number of pages11
JournalHuman Molecular Genetics
Volume22
Issue number12
DOIs
Publication statusPublished - 2013
Externally publishedYes

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