Hypoxia and XBP1S

RESEARCH HIGHLIGHTS

Nature Reviews Cancer | AOP, published online 10 April 2014; doi:10.1038/nrc3731

BREAST CANCER Further immunoprecipitation and cellular subfractionation studies indicated that XBP1S and HIF1α Hypoxia and XBP1S directly interact in the nucleus under hypoxic conditions and that they Tumour cells are subject to various was higher in basal breast cancer colocalize to several well-known cellular stresses during tumour cell lines (which mostly consist of HIF1 target genes. XBP1 or HIF1A evolution, including endoplasmic TNBC cells) and in biopsy samples knockdown using shRNAs indicated XBP1S is reticulum stress. Laurie Glimcher from patients with TNBC. Silencing that the loss of one factor affects the involved in and colleagues have found that the of XBP1 mRNA using short hairpin binding of the other to DNA and maintaining spliced form of X-box-binding pro- RNAs (shRNAs) inhibited colony prevents the recruitment of RNA tein 1 (XBP1S), which is activated as formation of TNBC cells in soft agar polymerase II, thereby preventing a cancer part of the unfolded protein response and the growth of orthotopic xeno- gene transcription. stem cell- (UPR), regulates a hypoxia-inducible grafts and metastases to the lung The authors also found that a like CD44high, factor 1α (HIF1α)-dependent trans in mice, which the authors showed 96‑gene signature of XBP1S activity CD24low criptional network in triple-negative was owing to a lack of angiogenesis. correlated with a hypoxia-driven breast cancer (TNBC) cells. Additional experiments showed that gene signature in TNBC cells. This population XBP1 is expressed in both basal XBP1S is involved in maintaining XBP1S gene signature was also and luminal breast cancer cell lines, a cancer stem cell-like CD44high, associated with a shorter relapse- but the expression level of XBP1S CD24low population. free survival time, as determined Chromatin immunoprecipitation using gene expression data from and DNA sequencing (ChIP–seq) two independent cohorts of patients experiments in a basal breast cancer with TNBC. cell line indicated that XBP1 and These findings indicate that, as HIF1α frequently colocalized to the part of the endoplasmic reticulum same regulatory DNA sequences. stress response, XBP1S maintains a HIF1α expression is known to be HIF1α‑driven hypoxic response in high in TNBC and is also required TNBC. These findings also indicate for the maintenance of the CD44high, that inhibitors of the UPR, combined CD24low population. Growth of with standard chemotherapy, might basal and luminal breast cancer cell improve the outcome in patients lines in low oxygen and glucose with TNBC. levels (conditions that mimic Nicola McCarthy ischaemia) increased the levels of ORIGINAL RESEARCH PAPER Chen, X. et al. XBP1S and its association with XBP1 promotes triple-negative breast cancer by HIF1α on chromatin in basal but controlling the HIF1α pathway. Nature 508, Lara Crow/NPG not luminal breast cancer cell lines. 103–107 (2014)

NATURE REVIEWS | CANCER VOLUME 14 | MAY 2014