TNBC growth is dependent on XBP1-mediated regulation of the HIF1α transcriptional program.
Major finding: TNBC growth is dependent on XBP1-mediated regulation of the HIF1α transcriptional program.
Mechanism: XBP1 forms a complex with HIF1α that recruits RNA polymerase II to HIF1α target genes.
Impact: Targeting the unfolded protein response pathway may be a potential treatment strategy for TNBC.
The unfolded protein response (UPR) is an adaptive mechanism that allows cancer cells to survive ER stress induced by the tumor microenvironment. UPR activation, regulated in part by the transcription factor X-box binding protein 1 (XBP1), has been reported in various human tumors, prompting Chen and colleagues to examine the role of XBP1 in triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with few treatment options. TNBC cell lines and primary patient samples exhibited significantly higher levels of the active spliced form of XBP1 than non-TNBC breast cancer samples, and knockdown of XBP1 impaired tumor growth and metastasis in a murine TNBC xenograft model. Moreover, XBP1 depletion inhibited TNBC xenograft tumor relapse when combined with doxorubicin and reduced the frequency, tumor-seeding capacity, and mammosphere formation ability of CD44high/CD24low stem-like cells, which have been implicated in TNBC relapse. Interestingly, XBP1 chromatin immunoprecipitation analysis revealed a significant enrichment of hypoxia-inducible factor 1α (HIF1α) binding sites, suggesting that HIF1α and XBP1 might colocalize to the same regulatory elements. Consistent with this finding, HIF1α and XBP1 were found to physically interact, and XBP1 depletion impaired the transcription of a HIF1α reporter and downregulated the expression of numerous HIF1α target genes by attenuating HIF1α and RNA polymerase II recruitment. Overexpression of constitutively active HIF1α in XBP1-depleted cells restored expression of HIF1α targets and TNBC tumor xenograft growth, indicating that HIF1α and XBP1 act as coregulators to sustain the HIF1α transcriptional program required for TNBC cells to overcome the hypoxic tumor microenvironment. Notably, expression of an XBP1-induced gene signature was correlated with decreased relapse-free survival in two independent cohorts of TNBC patients, but was not associated with clinical outcome in other breast cancer subtypes. These findings highlight an important function for XBP1 in TNBC progression and provide a rationale for clinical evaluation of UPR inhibitors in patients with TNBC.