title: LRH-1 governs vital transcriptional programs in endocrine-sensitive and -resistant breast cancer cells.
abstract: Tumor characteristics are decisive in the determination of treatment strategy for patients with breast cancer. Patients with estrogen receptor α (ERα)-positive breast cancer can benefit from long-term hormonal treatment. Nonetheless, the majority of patients will develop resistance to these therapies. Here, we investigated the role of the nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in antiestrogen-sensitive and -resistant breast cancer cells. We identified genome-wide LRH-1-binding sites using ChIP-seq (chromatin immunoprecipitation sequencing), uncovering preferential binding to regions distal to transcriptional start sites. We further characterized these LRH-1-binding sites by integrating overlapping layers of specific chromatin marks, revealing that many LRH-1-binding sites are active and could be involved in long-range enhancer-promoter looping. Combined with transcriptome analysis of LRH-1-depleted cells, these results show that LRH-1 regulates specific subsets of genes involved in cell proliferation in antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with a signature of poor outcome and high-grade breast cancer tumors in vivo. Herein, we report the genome-wide location and molecular function of LRH-1 in breast cancer cells and reveal its therapeutic potential for the treatment of breast cancers, notably for tumors resistant to treatments currently used in therapies.
authors: Authors' Affiliations: Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada; and Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College Hammersmith, London, United Kingdom.
authors: Stéphanie
authors: S
authors: Bianco
authors: Mylène
authors: M
authors: Brunelle
authors: Maïka
authors: M
authors: Jangal
authors: Luca
authors: L
authors: Magnani
authors: Nicolas
authors: N
authors: Gévry
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D002843:Chromatin / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000502:physiology; D006801:Humans; D061986:MCF-7 Cells; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: C530104:CCND1 protein, human; D002843:Chromatin; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; C109584:GPER1 protein, human; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D019938:Cyclin D1