Grant: Operating Grant

Prostate cancer is one of the leading causes of cancer-related death in men, mainly due to the development of aggressive tumors insensitive to hormone-deprivation therapies (castration-resistant tumors). It is therefore crucial to understand how these tumors arise and how they can be fought. We have recently shown that the loss of the transcription factor GATA3 is an important event for tumor progression as enforced GATA3 expression in a mouse model of prostate cancer effectively prevents cancer progression. Interestingly, it can do so when it is expressed in the cell nucleus (where it normally works), but the tumors sometimes exclude GATA3 from the nucleus, which allows tumors to progress. We find an equivalent situation in human as most advanced tumors (castrate-resistant) either lose GATA3 expression or exclude it from the nucleus. We will follow up on these important findings by studying how GATA3 is retained outside the nucleus in advanced tumors. We will also use mouse models of cancer to determine the role of GATA3 in preventing tumor development, notably in the cell able to regenerate the prostate as evidence suggests they are the ones at the origin of the aggressive form of prostate cancer. The presence of GATA3 outside the nucleus in advanced tumors suggests a therapeutic strategy whereby GATA3 could be sent back in the nucleus to inactivate cancer-promoting signals and induce tumor cell differentiation or elimination. Our experiments will help design such therapeutic strategy by understanding how GATA3 is inactivated in tumors and what it normally does when functional.