XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.
XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.
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DOI：
10.1038/nature13119
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发表时间：
2014-04-03
期刊：
影响因子：
64.8
通讯作者：
Glimcher, Laurie H.
中科院分区：
文献类型：
--
作者：
Chen, Xi;Iliopoulos, Dimitrios;Zhang, Qing;Tang, Qianzi;Greenblatt, Matthew B.;Hatziapostolou, Maria;Lim, Elgene;Tam, Wai Leong;Ni, Min;Chen, Yiwen;Mai, Junhua;Shen, Haifa;Hu, Dorothy Z.;Adoro, Stanley;Hu, Bella;Song, Minkyung;Tan, Chen;Landis, Melissa D.;Ferrari, Mauro;Shin, Sandra J.;Brown, Myles;Chang, Jenny C.;Liu, X. Shirley;Glimcher, Laurie H.
癌细胞诱导一系列适应性反应途径，以在血管化不足的压力源面前生存。一种这样的适应性途径是未折叠蛋白（UPR）或内质网（ER）应激反应，其部分由ER定位的跨膜传感器IRE 1及其底物XBP 1介导。先前的研究报告了UPR在各种人类肿瘤中的激活，但XBP 1在乳腺上皮细胞癌症进展中的作用在很大程度上是未知的。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Her 2/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，我们报告说，XBP 1在TNBC中被激活，并在这种人类乳腺癌亚型的致瘤性和进展中起着关键作用。在乳腺癌细胞系模型中，XBP 1的耗竭抑制了肿瘤生长和肿瘤复发，并减少了CD 44高/CD 24低群体。已知缺氧诱导因子（HIF）1α在TNBC中过度活化。XBP 1转录调控网络的全基因组图谱显示，XBP 1通过与HIF 1 α组装转录复合物来驱动TNBC致瘤性，该转录复合物通过RNA聚合酶II的募集来调控HIF 1 α靶点的表达。对TNBC患者独立队列的分析显示，特异性XBP 1基因表达特征与HIF 1 α和缺氧驱动特征高度相关，并与不良预后密切相关。我们的研究结果揭示了TNBC中UPR的XBP 1分支的关键功能，并暗示靶向该途径可能为这种侵袭性乳腺癌亚型提供替代治疗策略。
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 and its substrate XBP1. Previous studies report UPR activation in various human tumors, but XBP1's role in cancer progression in mammary epithelial cells is largely unknown. Triple negative breast cancer (TNBC), a form of breast cancer in which tumor cells do not express the genes for estrogen receptor, progesterone receptor, and Her2/neu, is a highly aggressive malignancy with limited treatment options. Here, we report that XBP1 is activated in TNBC and plays a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumor growth and tumor relapse and reduced the CD44high/CD24low population. Hypoxia-inducing factor (HIF)1α 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 imply that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
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DOI：
10.1186/1756-9966-31-59
发表时间：
2012-07-04
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Lin Y;Zhong Y;Guan H;Zhang X;Sun Q
通讯作者：
Sun Q
影响因子：
11.2
作者：
Spiotto MT;Banh A;Papandreou I;Cao H;Galvez MG;Gurtner GC;Denko NC;Le QT;Koong AC
通讯作者：
Koong AC
影响因子：
50.3
作者：
Mahoney, Douglas J.;Lefebvre, Charles;Stojdl, David F.
通讯作者：
Stojdl, David F.
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
2.7
作者：
BARNARD, GA
通讯作者：
BARNARD, GA