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XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway

机译:XBP1通过控制HIF1α途径促进三阴性乳腺癌

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摘要

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)-a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)-is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44~(high)CD24~(low) population. Hypoxia-inducingfactor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIFla that regulates the expression of HIF1α targets via the recruitment ofRNA polymerase Ⅱ. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.%Laurie Glimcher及同事报告说,在"三阴乳腺癌"(TNBC)中,肿瘤细胞表现出内质网应激的基底水平升高和未折叠蛋白反应的XBP1分支(肿瘤微环境中的一个主要细胞应激反应通 道)被激活。TNBC肿瘤缺少雌激素、黄体酮和HER2的受体,这使得它们对于很多药物有抵抗力,因为没有药物作用目标。作者进而发现,在不缺氧情况下,XBP1在TNBC细胞系中 通过与HIF1发生相互作用并调控它来促进肿瘤形成。这项研究揭示了TNBC中两大应激通道之间的一个重要联系,并为这种侵袭性的乳腺癌提出了可能的治疗干预手段。
机译:由于血管化不足,癌细胞会诱导出一系列适应性反应途径,以面对应激源生存。一种这样的适应性途径是未折叠的蛋白质(UPR)或内质网(ER)应激反应,部分由ER定位的跨膜传感器IRE1(参考文献2)及其底物XBP1(参考文献3)介导。先前的研究报道了在各种人类肿瘤中的UPR激活,但是XBP1在乳腺上皮细胞癌进展中的作用尚不清楚。三阴性乳腺癌(TNBC)是一种乳腺癌,其中肿瘤细胞不表达雌激素受体,孕激素受体和HER2(也称为ERBB2或NEU)的基因,是一种高度侵袭性的恶性肿瘤,治疗选择有限。在这里我们报告XBP1在TNBC中被激活,并且在该人类乳腺癌亚型的致瘤性和进展中具有关键作用。在乳腺癌细胞系模型中,XBP1的耗竭抑制了肿瘤的生长和肿瘤的复发,并减少了CD44〜(高)CD24〜(低)细胞群。已知缺氧诱导因子1α(HIF1α)在TNBCs中被过度激活。 XBP1转录调控网络的全基因组图谱显示,XBP1通过与HIFla组装转录复合物来驱动TNBC致瘤性,该复合物通过募集RNA聚合酶Ⅱ来调节HIF1α靶标的表达。对TNBC患者的独立队列进行的分析显示,特定的XBP1基因表达特征与HIF1α和缺氧驱动的特征高度相关,并且与不良预后密切相关。我们的发现揭示了TNBC中UPR的XBP1分支的关键功能,并表明靶向这种途径可能为这种侵略性乳腺癌亚型提供替代治疗策略。%Laurie Glimcher和同事报告说,在“三阴乳腺癌”( TNBC)中,肿瘤细胞表现出内质网应激的基底水平升高和未折叠蛋白反应的XBP1分支(肿瘤微环境中的一个主要细胞应激反应通​​道)被激活。黄体酮和HER2的受体,这导致它们对于很多药物有抵抗力,因为没有药物作用目标。作者靴子发现,在不缺氧情况下,XBP1在TNBC细胞系中通过与HIF1发生相互作用并使其它研究发现了TNBC中两大应力通道之间的一个重要联系,并为这种侵袭性的并发症提出了可能的治疗干预手段。

著录项

  • 来源
    《Nature》 |2014年第7494期|103-107A1|共6页
  • 作者单位

    Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA,Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA;

    Centerfor Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA,Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China,Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Ya'an, Sichuan 625014, China;

    Departmentof Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;

    Centerfor Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA,Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02215, USA;

    Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA;

    Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA,Department of Cell and Developmental Biology,Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA;

    Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;

    Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA,Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA;

    Division of Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

    Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA,Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA;

    Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA,Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA;

    Houston Methodist Cancer Center, Houston, Texas 77030, USA;

    Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA,Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA;

    Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA;

    Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA,Houston Methodist Cancer Center, Houston, Texas 77030, USA;

    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02215, USA;

    Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA,Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA;

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