LRH-1 governs vital transcriptional programs in endocrine sensitive and resistant breast cancer cells: Expression profiling. Homo sapiens

Tumor characteristics are decisive in the determination of treatment strategy for breast cancer patients. 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 liver receptor homolog-1 (LRH-1, NR5A2) in anti-estrogen (AE) sensitive and resistant breast cancer cells. We identified genome-wide LRH-1 binding sites using ChIP-seq, uncovering preferential binding to regions distal to transcriptional start sites (TSS). 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 AE-sensitive and AE-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with signature of poor outcome breast cancer tumors in vivo. Herein 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. Overall design: Total RNA was obtained from two biological replicates of breast cancer cells MCF7, LCC2 and LCC9 transduced with LRH-1 shRNA (shLRH-1) or control shRNA (shCTL) lentiviruses.

肿瘤特征是乳腺癌患者治疗策略制定的决定性因素。雌激素受体α（estrogen receptor-α, ERα）阳性乳腺癌患者可从长期内分泌治疗中获益，然而多数患者最终会对这类治疗产生耐药性。本研究探讨了肝受体同源物1（liver receptor homolog-1, LRH-1, NR5A2）在抗雌激素（anti-estrogen, AE）敏感及耐药乳腺癌细胞中的作用。通过ChIP-seq技术，我们鉴定了全基因组范围内的LRH-1结合位点，发现其优先结合于转录起始位点（transcriptional start sites, TSS）远端区域。本研究进一步通过整合多层特异性染色质修饰数据对上述LRH-1结合位点进行表征，结果显示多数LRH-1结合位点处于激活状态，且可能参与远程增强子-启动子环化过程。结合LRH-1敲低细胞的转录组分析结果，本研究证实LRH-1可在抗雌激素敏感与耐药乳腺癌细胞中调控参与细胞增殖的特定基因子集。此外，LRH-1调控的转录程序与体内不良预后乳腺癌的分子特征高度相关。本研究报道了LRH-1在乳腺癌细胞中的全基因组定位与分子功能，并揭示了其在乳腺癌治疗中的潜在应用价值，尤其针对当前临床治疗耐药的肿瘤。实验整体设计：从经LRH-1靶向短发夹RNA（shLRH-1）或对照短发夹RNA（shCTL）慢病毒转导的MCF7、LCC2及LCC9乳腺癌细胞的两个生物学重复样本中提取总RNA。