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

Abstract

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization1. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE12 and its substrate XBP13. Previous studies report UPR activation in various human tumors4-6, 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 options7, 8. 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 9, 10. 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.

Dual Targeting of Hypoxia and Homologous Recombination Repair Dysfunction in Triple-Negative Breast Cancer

“…This approach builds on a strong mechanistic rationale; accumulating evidence supports the view that hypoxia is prevalent in, and contributes to, progression in TNBC (16)(17)(18)(19)(20)(21)(22)(23)(24), whereas exploiting HR dysfunction has been extensively studied in the context of cross-linking agents and synthetic lethal interactions with pharmacologic inhibition of PARP1/2 (45). Furthermore, simultaneously drugging hypoxia and HR dysfunction is made doubly attractive by the observation that ), and mean þ SEM of tumor volume is shown.…”

“…Although early definitive characterization of tumor hypoxia preceded molecular classification of breast cancer (15), recent compelling evidence across multiple technology platforms links hypoxia specifically with TN/BL subtypes, where it may negatively influence treatment outcome (16)(17)(18)(19)(20)(21)(22)(23)(24), raising the possibility that drugs targeted to tumor hypoxia may be an effective strategy for TNBC. Several classes of hypoxia-activated prodrugs (HAP) have been rationally developed to exploit tumor hypoxia (14).…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Cancer Elevated XBP1s expression is observed in many human tumors, including breast cancer (Davies et al 2008;Chen et al 2014), pancreatic adenocarcinomas (Romero-Ramirez et al 2009), multiple myeloma (Carrasco et al 2007), chronic lymphocytic leukemia (CLL) (Krysov et al 2014), and plasma cell malignancy (Maestre et al 2009), suggesting that Xbp1 is a proto-oncogene. Consistently, myeloma patients with higher amounts of XBP1s have a poorer overall survival (Bagratuni et al 2010), and the growth of Xbp1-deficient tumor cells is impaired in xenograft models (Romero-Ramirez et al 2004).…”

Elementary: breast cancer culprits leave their signatures on the double helix

“…Most of these genes have been previously associated with tumorigenesis in various cancer types, including breast cancer. [2][3][4][5][6] It would be interesting to know whether their expression is correlated with patient outcome or associated with specific molecular subtypes. In non-coding DNA, the authors reported that only three promoters showed more mutations than expected by chance (PLEKHS1, WDR74 and TBC1D12), consistent with the recent observation that the number of somatic mutations in promoter regions is lower in breast cancer compared with other cancer types.…”