Gata3 antagonizes cancer progression in Pten-deficient prostates.

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.

• Authors: Alana H T Nguyen, Mathieu Tremblay, Katharina Haigh, Ismaël Hervé Koumakpayi, Marilène Paquet, Pier Paolo Pandolfi, Anne-Marie Mes-Masson, Fred Saad, Jody J Haigh, Maxime Bouchard
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 22 Issue 12 Pg. 2400-10 (Jun 15 2013) ISSN: 1460-2083 [Electronic] England
• PMID: 23428429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GATA3 Transcription Factor
• Gata3 protein, mouse
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase

Topics

• Animals
• Down-Regulation
• Female
• GATA3 Transcription Factor (genetics, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• PTEN Phosphohydrolase (antagonists & inhibitors, deficiency, genetics)
• Prostate (metabolism)
• Prostatic Neoplasms (enzymology, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction
• Tumor Cells, Cultured