The transcription factor (TF), FoxA1 has been described as a pioneer factor, implicated in steroid receptor (SR) binding patterns. Classically it has been proposed that the pioneer factor model is a slow and static binding event. However, it has recently been described that the estrogen and glucocorticoid receptors (ER and GR), can regulate the binding patterns of each other in a mouse mammary cell line defined as dynamic assisted loading. Further, this phenomenon has been extending demonstrating that both ER and GR can recruit FoxA1 to specific binding sites associated with an increase in chromatin accessibility and fast DNA residence times. This was also associated with the absence of a DNaseI footprint for the initiating and secondary factor supporting the assisted loading model. To further investigate the molecular mechanism behind the dynamic assisted loading model we have characterized the binding and transcriptional landscape of ER and GR in a number of breast cancer cell line models. Genome wide analysis of ChIP and DNaseI hypersensitivity assays upon single and dual activation show that both SRs can recruit each other to a specific subset of binding sites associated with an increase in chromatin accessibility. Therefore, depending on the chromatin landscape, one factor functions as the initiating factor and the other the secondary factor. Further, RNA polymerase II (RNAP II), p300, and H3K27ac binding patterns are associated with the newly programed ER or GR binding sites. Together this suggests chromatin reorganization upon dual activation of either ER or GR (the initiating factors) and recruitment of the secondary factor (ER or GR) through an assisted loading mechanism. Further, we have demonstrated an association of the transcriptional machinery at these newly acquired binding sites at active enhancers. These results propose that many TFs in a given cell have the potential to affect the binding landscape of other TFs, depending on the chromatin context. In addition, this study has shifted our classical understanding of pioneer factors in breast cancer, demonstrating that not only can SRs alter the response of FoxA1 but also each other though highly dynamic and fast DNA interactions associated with active enhancers and transcription.

Citation Format: Erin Swinstead, Tina Miranda, Ville Paakinaho, Songjoon Beak, Gordon Hager. The reprogramming of the steroid receptor binding landscape at active enhancers is associated with a fast DNA residence time through a mechanism termed dynamic assisted loading in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5499. doi:10.1158/1538-7445.AM2017-5499