Nature2014-06-19 3:56 PM

XBP1在侵袭性乳腺癌中的作用 XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway

论文摘要 

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。

Abstract 

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 CD44highCD24low population. Hypoxia-inducing factor 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 HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA 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.

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