PBX1 Genomic Pioneer Function Drives ERα Signaling Underlying Progression in Breast Cancer

Altered transcriptional programs are a hallmark of diseases, yet how these are established is still ill-defined. PBX1 is a TALE homeodomain protein involved in the development of different types of cancers. The estrogen receptor alpha (ER alpha) is central to the development of two-thirds of all breast cancers. Here we demonstrate that PBX1 acts as a pioneer factor and is essential for the ER alpha-mediated transcriptional response driving aggressive tumors in breast cancer. Indeed, PBX1 expression correlates with ER alpha in primary breast tumors, and breast cancer cells depleted of PBX1 no longer proliferate following estrogen stimulation. Profiling PBX1 recruitment and chromatin accessibility across the genome of breast cancer cells through ChIP-seq and FAIRE-seq reveals that PBX1 is loaded and promotes chromatin openness at specific genomic locations through its capacity to read specific epigenetic signatures. Accordingly, PBX1 guides ER alpha recruitment to a specific subset of sites. Expression profiling studies demonstrate that PBX1 controls over 70% of the estrogen response. More importantly, the PBX1-dependent transcriptional program is associated with poor-outcome in breast cancer patients. Correspondingly, PBX1 expression alone can discriminate a priori the outcome in ER alpha-positive breast cancer patients. These features are markedly different from the previously characterized ER alpha-associated pioneer factor FoxA1. Indeed, PBX1 is the only pioneer factor identified to date that discriminates outcome such as metastasis in ER alpha-positive breast cancer patients. Together our results reveal that PBX1 is a novel pioneer factor defining aggressive ER alpha-positive breast tumors, as it guides ER alpha genomic activity to unique genomic regions promoting a transcriptional program favorable to breast cancer progression.