Endocrine Abstracts

Prostate cancer (PCa) patients are typically treated by androgen ablation therapies that ultimately fail when PCa enters in androgen-depletion independence (ADI), leading to metastasis and death. To develop better clinical treatments it is crucial to understand the mechanisms underlying progression towards ADI and metastasis. Using ChIP-seq technology, I will show how the forkhead factor FoxA1 precisely restricts the extension of the androgen receptor (AR) binding program maintaining as ‘dormant’ 75% of the potentially AR-regulated program. Once ‘awaked’ -when FoxA1 is absent-, this previously unknown AR-regulated gene program would promote the progression to aggressive PCa by potentially conferring metastatic properties to the cell, including cell motility and cell migration. Together, this cascade of events provides a potential direct link between FoxA1-dependent regulation of AR, progression to ADI, and metastatic behaviour. These studies show how fine modulation of transcription factor levels can drastically modify the complete set of directly-regulated gene programs, deriving in dramatic consequences for tumour progression.