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XBP1 promotes triple-negative breast cancer by controlling the HIF1? pathway.

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 CD44(high)CD24(low) population. Hypoxia-inducing factor 1? (HIF1?) 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 HIF1? that regulates the expression of HIF1? 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 HIF1? 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.

SUBMITTER: Chen X

PROVIDER: S-EPMC4105133 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Chen Xi X Iliopoulos Dimitrios D Zhang Qing Q Tang Qianzi Q Greenblatt Matthew B MB Hatziapostolou Maria M Lim Elgene E Tam Wai Leong WL Ni Min M Chen Yiwen Y Mai Junhua J Shen Haifa H Hu Dorothy Z DZ Adoro Stanley S Hu Bella B Song Minkyung M Tan Chen C Landis Melissa D MD Ferrari Mauro M Shin Sandra J SJ Brown Myles M Chang Jenny C JC Liu X Shirley XS Glimcher Laurie H LH

Nature 20140323 7494

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-neg ...[more]

PMID: 24670641

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Project description:Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKC?/?, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKC?/? signaling as a potential therapeutic target for TNBC. Our observations indicated that PKC?/? signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKC?/? expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKC?/? significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKC?/?-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGF? and IL1? could activate PKC?/? signaling in TNBC cells and depletion of PKC?/? impairs NF-?B p65 (RelA) nuclear localization. We observed that cytokine-PKC?/?-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKC?/? promote TNBC growth, invasion and metastasis. Thus, targeting PKC?/? signaling could be a therapeutic option for breast cancer, including the TNBC subtype.

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XBP1 promotes triple-negative breast cancer by controlling the HIF1? pathway.

Publications

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

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