The Unfolded Protein Response in Breast Cancer
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cancers Review The Unfolded Protein Response in Breast Cancer Eoghan P. McGrath 1,2 , Susan E. Logue 1,2 , Katarzyna Mnich 1,2 , Shane Deegan 1,2, Richard Jäger 3 , Adrienne M. Gorman 1,2 and Afshin Samali 1,2,* 1 Apoptosis Research Centre, National University of Ireland (NUI), Galway, University Road, Galway, H91 TK33 Galway, Ireland; [email protected] (E.P.M.); [email protected] (S.E.L.); [email protected] (K.M.); [email protected] (S.D.); [email protected] (A.M.G.) 2 School of Natural Sciences, NUI Galway, University Road, H91 TK33 Galway, Ireland 3 Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, 53359 Rheinbach, Germany; [email protected] * Correspondence: [email protected]; Tel.: +353-91-492440 Received: 3 August 2018; Accepted: 18 September 2018; Published: 21 September 2018 Abstract: 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. Keywords: breast cancer; endoplasmic reticulum (ER) stress; unfolded protein response (UPR); therapy; cell death; autophagy 1. Introduction Breast cancer encompasses a heterogeneous set of diseases with distinct prognoses, physiological and histological characteristics, and treatment options [1]. Different breast cancer subtypes are commonly diagnosed based on the histological expression of three receptor proteins: estrogen receptor (ESR1, also known as ERα), progesterone receptor (PGR), and human epidermal growth factor receptor 2 (HER2, also known as ERBB2), and by the differential expression of fifty select genes (PAM50) which infer the “intrinsic” subtype. Subtyping breast cancer based on these parameters informs the clinician on the best course of treatment for the patient and has led to great improvements in survival rates. In PAM50 analyses, tumours with a gene expression profile typical of luminal epithelial cells belong to the luminal subtype (of which there are two sub-categories), and are usually hormone receptor positive (ESR1+ PGR+). Most breast tumours are luminal and are often responsive to ESR1 modulators, like tamoxifen, or aromatase inhibitors such as anastrozole. HER2+ cancers overexpress HER2 and are generally treated with antibodies targeting HER2 alone, or in combination with chemotherapeutics. Tumors exhibiting a myoepithelial PAM50 profile are referred to as basal-like tumours and are usually triple negative breast cancers (TNBC) in that they do not express ESR1 and PGR and do not have amplified HER2 expression. TNBC patients have a relatively poor outcome compared to other subtypes and TNBC currently lacks a targeted therapy [2–4]. Cancers 2018, 10, 344; doi:10.3390/cancers10100344 www.mdpi.com/journal/cancers Cancers 2018, 10, 344 2 of 21 TheCancers current 2018, 10,toolbox x of therapies available in the clinic has resulted in a high percentage2 of 21 breast cancer patients going into remission following treatment. Unfortunately, the remission period for many patientsThe current is short-lived toolbox of and therapies is frequently available followed in the clinic by has the resulted reappearance in a high of percentage drug-resistant of breast tumour cancer patients going into remission following treatment. Unfortunately, the remission period for clones. Discovering and targeting mechanisms by which tumours acquire drug resistance is a primary many patients is short-lived and is frequently followed by the reappearance of drug-resistant tumour goal for the breast cancer field [5]. clones. Discovering and targeting mechanisms by which tumours acquire drug resistance is a Theprimary endoplasmic goal for the reticulumbreast cancer (ER) field is [5 a]. complex cellular organelle responsible for the folding and post-translationalThe endoplasmic processing reticulum (ER) of membrane is a complex bound cellular andorganelle secreted responsible proteins. for the Disruption folding and of ER homoeostasispost-translational can cause processing misfolded of proteinsmembrane to accumulatebound and secreted within theproteins. ER lumen. Disruption This conditionof ER is knownhomoeostasis as ER stress can and cause leads misfolded to the (normally) proteins to transient accumulate activation within ofthe a ER cellular lumen. stress This response condition referred is to asknown the unfolded as ER stress protein and response leads to (UPR).the (normally) While thetransi UPRent primarilyactivation worksof a cellular to reduce stress the response backlog of unfoldedreferred proteins to as the and unfolded restore ERprotein function, response severe (UPR or). prolongedWhile the UPR UPR primarily signals can works trigger to reduce cell death the [6]. 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Since the for UPR the developmentis normally inactive of novel in non breast-tumour cancer cells treatments.but active in tumour An added cells, benefit it is is that thea strong UPR candidate poses distinct for the therapeuticdevelopment possibilities of novel breast for cancer different treatments. breast An cancer added subtypes benefit is including that TNBC.the Therefore, UPR poses andistinct understanding therapeutic possibilities of UPR biology for different in oncology breast cancer and elucidation subtypes including of the potential TNBC. for UPR-targetingTherefore, drugsan understanding to improve of the UPR treatment biology ofin breastoncology cancer and iselucidation worth exploring. of the potential Recent for translational UPR- targeting drugs to improve the treatment of breast cancer is worth exploring. Recent translational UPR research has allowed us to gain insight into how the treatment of different breast cancer subtypes UPR research has allowed us to gain insight into how the treatment of different breast cancer can besubtypes improved. can be improved. FigureFigure 1. Multiple1. Multiple tumour-associated tumour-associated stressors stressors induce induce endoplasmic endoplasmic reticulum reticulum (ER) stress (ER) and stress pro- and pro-tumourtumour unfolded protein protein response response (UPR (UPR)) signalling signalling.. A variety A of variety cell intrinsic of cell and intrinsic extrinsic andstressors extrinsic lead to UPR activation. In turn the UPR drives multiple pro-tumour processes associated with worse stressors lead to UPR activation. In turn the UPR drives multiple pro-tumour processes associated with patient outcome. worse patient outcome. Cancers 2018, 10, x 4 of 21 Cancers 2018, 10, 344 3 of 21 ATF6 is believed to primarily promote cell survival. Upon ER stress ATF6 translocates from the 2.ER The membrane Unfolded to Proteinthe Golgi Reponses where it is cleaved by site-1 and site-2 proteases. Cleaved ATF6 (ATF6f) then moves to the nucleus where it promotes expression of XBP1, GRP78, and ER-localized chaperonesUPR signalling to promote originates protein from folding three and sensor ER homeostasis proteins which (See traverse Figure 2 the). Though ER membrane; ATF6 signaling Inositol Requiringpredominantly Enzyme promotes 1 (IRE1, survival, also it known has also as been ERN1), linked Activating indirectly Transcription to the downregulation Factor 6 (ATF6),of pro- andsurvival PKR-like BCL-2 ER family Kinase member (PERK, myeloid also known cell leukemia as EIF2AK3). 1 (MCL1) Under [10,19,20] non-stressed. conditions all three sensorsProlonged are bound and/or by theintense chaperone ER stress glucose is lethal regulated to normal protein cells, 78but kDa in cancer (GRP78, UPR also signaling known i ass both BiP orsustained