Transcriptome analysis of luminal breast cancer reveals a role for LOL in tumor progression and tamoxifen resistance
Transcriptome analysis of luminal breast cancer reveals a role for LOL in tumor progression and tamoxifen resistance
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管腔乳腺癌的转录组分析揭示了 LOL 在肿瘤进展和他莫昔芬耐药中的作用
DOI：
10.1002/ijc.32185
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发表时间：
2019
影响因子：
6.4
通讯作者：
Shao Zhiming
中科院分区：
文献类型：
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作者：
Sun Wei;Xu Xiaoen;Jiang Yizhou;Jin Xi;Zhou Ping;Liu Yirong;Guo Yajie;Ma Ding;Zuo Wenjia;Huang Shenglin;He Xianghuo;Shao Zhiming
腔内乳腺癌（BC）具有持续的晚期疾病复发和死亡风险。相当多的患者出现抗内分泌治疗抵抗。在这里，我们发现了一种新的lncRNA，它在乳腺癌中表达高，特别是在管腔乳腺癌中表达高，被称为LOL（管腔lncRNA），它作为let‐7 microrna的天然海绵，调节肿瘤生长和他莫昔芬耐药性。与阴性对照相比，添加他莫昔芬后，亲代MCF - 7细胞中LOL过表达表现出增殖优势。降低TamR MCF‐7细胞中的LOL，恢复细胞对他莫昔芬的敏感性。引人注目的是，我们证明了LOL是从一个增强子的基因组位点转录而来，以维持其在腔内BC中的高表达，并且它对增强子调节因子（如ZMYND8和BRD4）极其敏感。雌激素剥夺或ERα信号通路阻断可进一步刺激LOL表达，促进肿瘤进展。374例腔内乳腺癌样本的临床分析表明，LOL是腔内BC患者生存不良的独立预后因素。总之，使用BRD4抑制剂等临床前/临床药物靶向LOL可能是抑制腔内乳腺癌进展和他莫昔芬耐药的一种有希望的方法。
Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from antiendocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let‐7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF‐7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF‐7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer‐regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.