Estrogen receptor (ER) is the defining feature of luminal breast cancers, where it functions as a transcription factor. ER requires associated proteins to interact with the DNA, including the pioneer factors FoxA1 and GATA3, both of which mediate where in the genome ER resides. In the absence of FoxA1, ER binding and transcriptional activity is diminished, even in endocrine resistant contexts. We have utilized ChIP-seq in primary tumor material, coupled with functional analysis, to identify mechanisms that govern FoxA1-ER DNA interactions and the variables that alter binding capacity. Based on these findings, we have screened chemical libraries to identify specific inhibitors of FoxA1, with the goal of blocking ER function via inhibition of its associated pioneer factor. In addition, we have sought to discover novel ER associated proteins that are involved in endocrine resistance and to achieve this, we have established a method for rapid unbiased discovery of protein interacting complexes, which we have applied to discover ER and FoxA1 associated proteins. We find an unexpected interaction between ER and progesterone receptor (PR) in ER+ breast cancer. We show that PR is a negative regulator of the ER complex, where it is important for modulating cellular growth. Our findings suggest that there is substantial cross-talk between parallel hormonal pathways and that we can use this information to repurpose existing steroid receptor ligands for therapeutic use.
28 - 31 May 2016
European Society of Endocrinology