title: 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: Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3A 1A3.
authors: Alana H T
authors: AH
authors: Nguyen
authors: Mathieu
authors: M
authors: Tremblay
authors: Katharina
authors: K
authors: Haigh
authors: Ismaël Hervé
authors: IH
authors: Koumakpayi
authors: Marilène
authors: M
authors: Paquet
authors: Pier Paolo
authors: PP
authors: Pandolfi
authors: Anne-Marie
authors: AM
authors: Mes-Masson
authors: Fred
authors: F
authors: Saad
authors: Jody J
authors: JJ
authors: Haigh
authors: Maxime
authors: M
authors: Bouchard
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase