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管腔型（激素受体阳性）乳腺癌的疾病复发和死亡风险长期存在，而且相当一部分患者对内分泌治疗药物（例如他莫昔芬）发生耐药。 2019年2月19日，国际抗癌联盟《国际癌症杂志》清样发表复旦大学附属肿瘤医院孙伟、徐晓恩、江一舟、金希、刘依熔、郭雅洁、马丁、左文佳、黄胜林、何祥火、邵志敏等学者的研究报告，通过转录组分析发现一种管腔型长链非编码核糖核酸（LOL）对管腔型乳腺癌肿瘤进展和他莫昔芬耐药的作用。 该研究发现LOL高表达于乳腺癌，尤其管腔型乳腺癌，作为致死基因7（let-7）小分子核糖核酸的天然海绵样载体，可以控制肿瘤生长和他莫昔芬耐药。LOL过表达的激素受体阳性HER2阴性乳腺癌亲代细胞株（MCF-7）与LOL阴性对照细胞相比，加入他莫昔芬后的细胞繁殖能力较强。抑制他莫昔芬耐药MCF-7细胞的LOL表达后，可以恢复细胞对他莫昔芬的敏感性。重要的是，该研究证实LOL由增强子基因组位点转录而来，可以维持其高表达于管腔乳腺癌，并且对增强子调节因子如ZMYND8和BRD4极其敏感。抑制雌激素或阻断雌激素受体α信号转导通路，可以进一步刺激LOL表达，从而促进肿瘤进展。此外，根据对374例管腔型乳腺癌标本的临床分析表明，LOL是管腔型乳腺癌生存不佳的独立预后因素，无论其他预后因素如何。 因此，该研究结果表明，通过临床前或临床药物（例如BRD4抑制剂）靶向LOL，有望成为抑制管腔乳腺癌进展和他莫昔芬耐药的新方法。 Int J Cancer. 2019 Feb 19. [Epub ahead of print] Transcriptome analysis of Luminal Breast Cancer Reveals a Role for LOL in Tumor Progression and Tamoxifen Resistance. Sun W, Xu X, Jiang Y, Jin X, Zhou P, Liu Y, Guo Y, Ma D, Zuo W, Huang S, He X, Shao Z. Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; The Third Hospital of Nanchang, Nanchang, Jiangxi, China. 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. PMID: 30720865 DOI: 10.1002/ijc.32185
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