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In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies.
The endoplasmic reticulum (ER) is a major cellular organelle consisting of a vast reticular network spanning from the nuclear envelope to the plasma membrane. It plays a major role in various cellular processes including protein synthesis and glycosylation, the secretory pathway, and membrane biogenesis. It is sensitive to changes in its lumenal homeostasis. Loss of ER lumenal homeostasis leads to a condition referred to as ER stress. The cellular response to ER stress is to orchestrate the activation of an evolutionarily conserved transcriptional program termed the unfolded protein response (UPR). A consequence of UPR is upregulation of the components of the autophagic machinery and increased autophagic flux. Over the past decade much research investigating the onset and progression of autophagy following activation of the UPR has been carried out. Owing to this we now have a better understanding of the signaling pathways leading to ER stress-mediated autophagy and have begun to appreciate the importance of the ER localized stress sensors, IRE1, ATF6, and PERK in this process. In this chapter we provide an overview of the current thinking concerning the role of ER stress and UPR in initiation and regulation of autophagy.
Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.
