1] Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland [2] Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.
Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
Oncogene. 2015 Jul;34(29):3871-80. doi: 10.1038/onc.2014.323. Epub 2014 Oct 6.
Breast cancer resistance to endocrine therapies such as tamoxifen and aromatase inhibitors is a significant clinical problem. Steroid receptor coactivator-1 (SRC-1), a coregulatory protein of the oestrogen receptor (ER), has previously been shown to have a significant role in the progression of breast cancer. The chromatin protein high mobility group box 2 (HMGB2) was identified as an SRC-1 interacting protein in the endocrine-resistant setting. We investigated the expression of HMGB2 in a cohort of 1068 breast cancer patients and found an association with increased disease-free survival time in patients treated with endocrine therapy. However, it was also verified that HMGB2 expression could be switched on in endocrine-resistant tumours from breast cancer patients. To explore the function of this poorly characterized protein, we performed HMGB2 ChIPseq and found distinct binding patterns between the two contexts. In the resistant setting, the HMGB2, SRC-1 and ER complex are enriched at promoter regions of target genes, with bioinformatic analysis indicating a switch in binding partners between the sensitive and resistant phenotypes. Integration of binding and gene expression data reveals a concise set of target genes of this complex including the RNA helicase DDX18. Modulation of DDX18 directly affects growth of tamoxifen-resistant cells, suggesting that it may be a critical downstream effector of the HMGB2:ER complex. This study defines HMGB2 interactions with the ER complex at specific target genes in the tamoxifen-resistant setting.
乳腺癌对他莫昔芬和芳香化酶抑制剂等内分泌治疗的耐药性是一个重大的临床问题。类固醇受体共激活因子-1（SRC-1）是雌激素受体（ER）的核心调节蛋白，先前已被证明在乳腺癌的进展中具有重要作用。染色质蛋白高迁移率族蛋白 B2（HMGB2）在内分泌耐药环境中被鉴定为 SRC-1 的相互作用蛋白。我们调查了 1068 例乳腺癌患者队列中 HMGB2 的表达情况，发现其与接受内分泌治疗的患者无病生存时间延长有关。然而，也证实 HMGB2 的表达可以在来自乳腺癌患者的内分泌耐药肿瘤中被激活。为了探索这种特征不明确的蛋白质的功能，我们进行了 HMGB2 ChIPseq，发现两种情况下的结合模式存在明显差异。在耐药环境中，HMGB2、SRC-1 和 ER 复合物富集在靶基因的启动子区域，生物信息学分析表明在敏感和耐药表型之间结合伴侣发生了转换。结合和基因表达数据的整合揭示了该复合物的一组简洁的靶基因，包括 RNA 解旋酶 DDX18。DDX18 的调节直接影响他莫昔芬耐药细胞的生长，表明它可能是 HMGB2:ER 复合物的关键下游效应因子。这项研究定义了 HMGB2 在他莫昔芬耐药环境中与 ER 复合物在特定靶基因上的相互作用。
