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The tumor suppressor gene  PTEN  (phosphatase and tensin homolog deleted on chromosome 10) plays important roles in tumor development and progression. Among many functions, PTEN negatively regulates the AKT anti-apoptotic signaling pathway, while nuclear PTEN affects the cell cycle by repressing the mitogen-activated protein kinase pathway. However, the regulation of  PTEN  expression is still not well understood. We previously reported that androgen receptor (AR) activates  PTEN  transcription in breast cancer cells. Here, we found that the transcription factor GATA2 (GATA binding protein 2) is overexpressed in non-cultured human breast carcinomas and is negatively correlated with  PTEN  expression. We then showed GATA2 promotes breast cancer cell growth and stimulates AKT phosphorylation by inhibiting  PTEN  transcription. We mapped a GATA2-binding site in the  PTEN  promoter, whereby GATA2 not only blocks AR-induced  PTEN  expression by preventing AR nuclear translocation, but also directly represses  PTEN  transcription independent of AR. Most importantly, for the first time, we have discovered a novel reverse regulation within the traditional PTEN/AKT signaling pathway, whereby AKT induces GATA2 with consequent decreased  PTEN  transcription, likely germane in tumor invasion and metastases but not initiation.

human molecular genetics

GATA2 negatively regulates PTEN by preventing nuclear translocation of androgen receptor and by androgen-independent suppression of  PTEN  transcription in breast cancer