Sun Ge, Zhao Chunguang, Han Jing, Wu Shaoya, Chen Yan, Yao Jing, Li Li
Gene Regulation and Diseases Lab, College of Life Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, PR China.
Department of Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, Hunan Province, 410008, China.
Cell Oncol (Dordr). 2024 Dec;47(6):2073-2090. doi: 10.1007/s13402-024-01011-y. Epub 2024 Nov 14.
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.
类固醇激素受体（SHRs）对转录重编程的调控对于乳腺癌进展至关重要。SHRs，包括雌激素受体（ER）、雄激素受体（AR）、孕激素受体（PR）和糖皮质激素受体（GR），在重塑乳腺癌细胞转录组中发挥关键作用。然而，SHRs在增强子区域调控染色质格局以及转录因子相互作用的分子机制在很大程度上仍不清楚。在本综述中，我们总结了3种SHRs（AR、PR和GR）通过染色质相互作用和增强子重编程对基因转录的调控作用。具体而言，AR和PR对ER介导的基因转录表现出双向调控作用（抑制和促进），而GR调节ER阳性乳腺癌细胞中促增殖基因的转录。此外，我们还介绍了四种增强子重编程机制（转录因子合作、先锋因子结合、动态辅助加载和拴系）以及多种增强子-启动子接触模型。基于这些机制和模型，本综述提出，SHRs激动剂/拮抗剂加内分泌治疗等多种治疗策略的联合应用以及采用最新的测序技术有望提高ER阳性乳腺癌的治疗效果。
