Tumour cells endure both oncogenic and environmental stresses during cancer progression. Transformed cells must meet increased demands for protein and lipid production needed for rapid proliferation and must adapt to exist in an oxygen‐ and nutrient‐deprived environment. To overcome such challenges, cancer cells exploit intrinsic adaptive mechanisms such as the unfolded protein response (UPR). The UPR is a pro‐survival mechanism triggered by accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), a condition referred to as ER stress. IRE1, PERK and ATF6 are three ER anchored transmembrane receptors. Upon induction of ER stress, they signal in a coordinated fashion to re‐establish ER homoeostasis, thus aiding cell survival. Over the past decade, evidence has emerged supporting a role for the UPR in the establishment and progression of several cancers, including breast cancer, prostate cancer and glioblastoma multiforme. This review discusses our current knowledge of the UPR during oncogenesis, tumour growth, metastasis and chemoresistance.

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.

Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity. Mechanisms of Tumour Chemoresistance and Relapse: Emerging Role of the Tumour Cell SecretomeChemotherapy is a common and successful therapeutic strategy for many patients with cancer as a neoadjuvant or adjuvant treatment to surgery. However, a significant number of patients relapse months or years later with a tumour that is resistant to further chemotherapeutic challenge, a feature known as chemoresistance. Many relapsing tumours are also associated with distant metastasis, which is the leading cause of cancer-related deaths [1,2]. Therefore, it is critical to identify the mechanisms of chemoresistance to develop targeted therapies and improve the rate of relapsefree survival. Chemoresistance occurs through two mechanisms: intrinsic and acquired resistance. Intrinsic or inherent resistance arises in tumour cells harbouring mutations in cellular processes that prime the cell for survival during chemotherapy treatment. Cancer cells undergoing chemotherapy can also develop or acquire resistance through additional genetic modification or rewiring of intracellular signalling pathways that are known to be crucial for drug resistance [3]. Several key cellular processes are involved in the development of chemoresistance, including drug activation or inactivation, DNA damage repair, modifications to drug targets, enhanced drug efflux, inactivation of apoptosis machinery, and increased autophagy [3,4].Tumour heterogeneity also contributes to a resistant phenotype due to the presence of genetically diverse clones within a tumour. Each of these populations may respond differently to treatment, resulting in the emergence of drug resistant clones. CSCs are a small subpopulation of cancer cells found within the tumour that are another cellular source of chemoresistance. These cells have similar characteristics to nontransformed stem cells, such as the ability to selfrenew, express the embryonic factors Oct4, Sox2, and Nanog, and are capable of differentiating into committed tumour cells. Due to their inherent quiescent state, CSCs can evade the actions of drugs that target rapidly proliferating cells, and can limit drug toxicity due to increased expression of aldehyde dehydrogenase (ALDH), drug e...