Regulatory mechanisms of steroid hormone receptors on gene transcription through chromatin interaction and enhancer reprogramming.

Regulation of steroid hormone receptors (SHRs) on transcriptional reprogramming is crucial for breast cancer progression. SHRs, including estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) play key roles in remodeling the transcriptome of breast cancer cells. However, the molecular mechanisms by which SHRs regulate chromatin landscape in enhancer regions and transcription factor interactions remain largely unknown. In this review, we summarized the regulatory effects of 3 types of SHRs (AR, PR, and GR) on gene transcription through chromatin interactions and enhancer reprogramming. Specifically, AR and PR exhibit bi-directional regulatory effects (both inhibitory and promoting) on ER-mediated gene transcription, while GR modulates the transcription of pro-proliferation genes in ER-positive breast cancer cells. In addition, we have presented four enhancer reprogramming mechanisms (transcription factor cooperation, pioneer factor binding, dynamic assisted loading, and tethering) and the multiple enhancer-promoter contact models. Based on these mechanisms and models, this review proposes that the combination of multiple therapy strategies such as agonists/antagonists of SHRs plus endocrine therapy and the adoption of the latest sequencing technologies are expected to improve the efficacy of ER positive breast cancer treatment.