Abstract
Nuclear receptors (NRs) orchestrate transcriptional programs that regulate cell fate decisions, and when these processes are disrupted, they can drive hormone-dependent cancers. This review summarizes mechanisms by which NRs function collectively, or crosstalk, to bring about the complex transcriptional control of cell fate decisions and indicate where these processes can act as cancer drivers. These crosstalk mechanisms include the exchange of coregulators between NRs and as well as genomic convergence of NRs. Evidence is also discussed for how NRs potentially pass through a continuum of interactions as part of a biological ratchet mechanism to regulate gene transcription. In this continuum, pioneer factors drive chromatin competence for NRs and, along with mammalian SWI/SNF complexes, facilitate transient assisted loading between NRs, as well as more stable crosstalk in the form of mitotic bookmarking, which allows inheritance of transcriptional control. NR crosstalk is also sustained through the function of larger and perhaps more stable interactions, such as through the megatrans complex. Also considered to explain NR crosstalk is the established and emerging understanding of the grammar of motif selection, and this is placed in the context of NR network approaches, for example in breast cancer. Finally, a systems-level framework, called NuRome, is discussed that combines high-dimensional data at the cistrome, transcriptome, and proteome levels to provide a predictive understanding of NR crosstalk and transcription in cancer.