Khaled Walid T, Choon Lee Song, Stingl John, Chen Xiongfeng, Raza Ali H, Rueda Oscar M, Hadi Fazal, Wang Juexuan, Yu Yong, Chin Suet-Feung, Stratton Mike, Futreal Andy, Jenkins Nancy A, Aparicio Sam, Copeland Neal G, Watson Christine J, Caldas Carlos, Liu Pentao
1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK [2] Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK [3].
1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK [2].
Nat Commun. 2015 Jan 9;6:5987. doi: 10.1038/ncomms6987.
Triple-negative breast cancer (TNBC) has poor prognostic outcome compared with other types of breast cancer. The molecular and cellular mechanisms underlying TNBC pathology are not fully understood. Here, we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. Exogenous BCL11A overexpression promotes tumour formation, whereas its knockdown in TNBC cell lines suppresses their tumourigenic potential in xenograft models. In the DMBA-induced tumour model, Bcl11a deletion substantially decreases tumour formation, even in p53-null cells and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, Bcl11a deletion causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in TNBC and normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in TNBC-targeted therapies.
与其他类型的乳腺癌相比，三阴性乳腺癌（TNBC）的预后较差。TNBC病理背后的分子和细胞机制尚未完全了解。在此，我们报告转录因子BCL11A在包括基底样乳腺癌（BLBC）在内的TNBC中过表达，并且其基因组位点在高达38%的BLBC肿瘤中发生扩增。外源性BCL11A过表达促进肿瘤形成，而在TNBC细胞系中敲低它则会抑制其在异种移植模型中的致瘤潜力。在二甲基苯并蒽（DMBA）诱导的肿瘤模型中，Bcl11a缺失显著减少肿瘤形成，即使在p53基因缺失的细胞中也是如此，并且在已形成的肿瘤中使Bcl11a失活会导致肿瘤消退。在细胞水平上，Bcl11a缺失导致乳腺上皮干细胞和祖细胞数量减少。因此，BCL11A在TNBC和正常乳腺上皮细胞中具有重要作用。这项研究突出了在TNBC靶向治疗中进一步研究BCL11A的重要性。
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