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      Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance

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          Abstract

          The unfolded protein response (UPR) is a stress response activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) and its uncontrolled activation is mechanistically responsible for several human pathologies, including metabolic, neurodegenerative, and inflammatory diseases, and cancer. Indeed, ER stress and the downstream UPR activation lead to changes in the levels and activities of key regulators of cell survival and autophagy and this is physiologically finalized to restore metabolic homeostasis with the integration of pro-death or/and pro-survival signals. By contrast, the chronic activation of UPR in cancer cells is widely considered a mechanism of tumor progression. In this review, we focus on the relationship between ER stress, apoptosis, and autophagy in human breast cancer and the interplay between the activation of UPR and resistance to anticancer therapies with the aim to disclose novel therapeutic scenarios. The hypothesis that autophagy and UPR may provide novel molecular targets in human malignancies is discussed.

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          The integrated stress response.

          Karolina Pakos-Zebrucka, Izabela Koryga, Katarzyna Mnich … (2016)
          In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli. Although the ISR is primarily a pro-survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress.
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            ER stress-induced cell death mechanisms.

            Renata Sano, John C. Reed (2013)
            The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Section entitled: Cell Death Pathways. © 2013.
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              CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.

              H Zinszner, M Kuroda, X. Wang … (1998)
              Cellular stress, particularly in response to toxic and metabolic insults that perturb function of the endoplasmic reticulum (ER stress), is a powerful inducer of the transcription factor CHOP. The role of CHOP in the response of cells to injury associated with ER stress was examined in a murine deficiency model obtained by homologous recombination at the chop gene. Compared with the wild type, mouse embryonic fibroblasts (MEFs) derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER function. A similar deficit in programmed cells death in response to ER stress was also observed in MEFs that lack CHOP's major dimerization partner, C/EBPbeta, implicating the CHOP-C/EBP pathway in programmed cell death. An animal model for studying the effects of chop on the response to ER stress was developed. It entailed exposing mice with defined chop genotypes to a single sublethal intraperitoneal injection of tunicamycin and resulted in a severe illness characterized by transient renal insufficiency. In chop +/+ and chop +/- mice this was associated with the early expression of CHOP in the proximal tubules followed by the development of a histological picture similar to the human condition known as acute tubular necrosis, a process that resolved by cellular regeneration. In the chop -/- animals, in spite of the severe impairment in renal function, evidence of cellular death in the kidney was reduced compared with the wild type. The proximal tubule epithelium of chop -/- animals exhibited fourfold lower levels of TUNEL-positive cells (a marker for programmed cell death), and significantly less evidence for subsequent regeneration. CHOP therefore has a role in the induction of cell death under conditions associated with malfunction of the ER and may also have a role in cellular regeneration under such circumstances.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 16 February 2019
                Publication date Collection: February 2019
                Volume: 20
                Issue: 4
                Electronic Location Identifier: 857
                Affiliations
                [1 ]Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy; lorisi@ 123456hotmail.com (L.S.); michele.pietrafesa@ 123456crob.it (M.P.); silvia.lepore@ 123456crob.it (S.L.); francesca.maddalena@ 123456crob.it (F.M.); valentina.condelli@ 123456crob.it (V.C.)
                [2 ]Department of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, 80131 Naples, Italy; franca.esposito@ 123456unina.it
                [3 ]Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy
                Author notes
                [* ]Correspondence: matteo.landriscina@ 123456unifg.it ; Tel.: +39-0881-736426
                [†]

                These authors contributed equally.

                Author information
                https://orcid.org/0000-0001-9340-6875
                https://orcid.org/0000-0003-0591-9799
                Article
                Publisher ID: ijms-20-00857
                DOI: 10.3390/ijms20040857
                PMC ID: 6412864
                PubMed ID: 30781465
                SO-VID: 9c4b567d-d2b4-481f-b618-81ab9b7c8df1
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 14 January 2019
                Date accepted : 15 February 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: endoplasmic reticulum stress,unfolded protein response,breast cancer,apoptosis,autophagy,drug resistance,hormone therapy
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: endoplasmic reticulum stress, unfolded protein response, breast cancer, apoptosis, autophagy, drug resistance, hormone therapy

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