By Asu Erden
Triple negative breast cancers are highly aggressive malignancies. They do not express any of the hormone receptors usually used to target chemotherapies to treat this type of cancer and have a high relapse rate after treatment. As such, these cancers can come with a very poor prognosis and insight into their development is therefore direly needed. A study published this month by Chen et al. in the scientific journal Nature dissects the role of the XBP1 protein in the development of triple negative breast cancers. The team of scientists from Weill Cornell Medical College observed that XBP1 levels are higher in triple negative breast cancer cell lines. Of particular therapeutic relevance is their finding that depleting XBP1 leads to reduced tumor metastasis in both a mouse model of triple negative breast cancer and human cell lines derived from such cancers. These findings offer hope for the development of therapies aimed at treating this highly challenging cancer.
Cancers have high proliferative rates. This incurs a high energetic cost on cells by requiring the rapid synthesis of proteins. The resulting accumulation of unfolded proteins can in time lead to cellular stress. Studies have shown that the unfolded protein response (UPR) is activated in most breast cancers. The UPR is a cellular stress response mediated by the enzyme IRE1. The role of this enzyme is to cut up the Xbp1 mRNA into its mature form and allow the activated XBP1 protein to translocate to the nucleus. There, XBP1 acts as a transcription factor and allows the expression of a host of genes involved in the UPR.
To investigate the effects of anti-XBP1 treatment on cancer relapse, Chen et al. treated a breast cancer mouse model with a combination of XBP1 short-hairpin RNA (shRNA) and doxorubicin (a chemotherapeutic drug). XBP1 shRNA prevent the expression of the XBP1 gene. This combination therapy prevented tumor growth and relapse. Further probing revealed that XBP1 shRNA acts by targeting a specific tumor cell subset – human breast cancer stem cells – known to be involved in tumor relapse. Isolation of this cell population from triple negative breast cancer patients revealed increased levels of activated XBP1. Moreover, the silencing of XBP1 in these mammary gland cells resulted in reduced cell clumps, while overexpression of this gene resulted in increased cell clump formation and resistance to chemotherapeutic drugs.
Chen’s team also further dissected the mechanism allowing XBP1 to promote the development of triple negative breast cancers. They unraveled the protein’s involvement in the hypoxia-induced cellular stress response. Hypoxia – a condition characterized by a deficiency in the amount of oxygen reaching cells – is a potent cellular stressor. It is also a central feature of many tumors. The hypoxia-induced factor 1a (HIF1a) is activated during the cellular response to hypoxia and is known to be upregulated in triple negative breast cancers. Chen et al. shed light on the interplay between XBP1 and HIF1a, which was hitherto unknown. They revealed that the two proteins cooperate in targeting specific DNA sequences and that XBP1 increases HIF1a activity. XBP1 therefore allows the hypoxia response, characteristic of cancers, to take place by promoting the cellular responses mediated by HIF1a.
The results from this study shed light on the mechanism through which XBP1 contributes to the development of triple negative breast cancers. Of particular note is Chen et al.’s silencing data. Therapies utilizing XBP1 silencing techniques, such as shRNAs, combined with chemotherapies could result in highly successful clearance of these cancers and significantly reduced chances of relapse.