Scriven, P., Coulson, S., Haines, R. et al. (3 more authors) (2009) Activation and clinical significance of the unfolded protein response in breast cancer. British Journal of Cancer , 101 (10). pp. 1692-1698. ISSN 0007-0920
Abstract
introduction: The tumour microenvironment is hypoglycaemic, hypoxic and acidotic. This activates a stress signalling pathway: the unfolded protein response (UPR). The UPR is cytoprotective if the stressor is mild, but may initiate apoptosis if severe.Activation of the UPR in breast carcinoma is induced by microenvironmental stress such as glucose and oxygen deprivation, but may also be linked to oestrogen stimulation. It may be clinically significant as it may alter chemosensitivity to doxorubicin. methods: 395 human breast adenocarcinomas were immunohistochemically stained for UPR activation markers (glucose-regulated protein (GRP-78 and XBP-1). A model of UPR activation in vitro by glucose deprivation of T47D breast cancer cells was developed to determine how the UPR affects cellular sensitivity to doxorubicin and 5-fluorouracil. Cytotoxicity was assessed using a colorimetric cytotoxicity assay (MTT). The effect of oestrogen stimulation and tamoxifen exposure on UPR activation by T47D cells was determined by western blotting measurement of the key UPR protein, GRP-78. results: Expression of GRP78 and XBP-1 was demonstrated in 76% and 90% of the breast cancers, respectively, and correlated with oestrogen receptor positivity (P=0.045 and 0.017, respectively). In vitro UPR activation induced resistance to both doxorubicin and 5-flurouracil, (P<0.05). Oestrogen stimulation induced GRP78 and XBP1 over-expression on western blotting. Tamoxifen did not block this response and may induce UPR activation in its own right. conclusions: The UPR is activated in the majority of breast cancers and confers resistance to chemotherapy. In vitro oestrogen stimulates UPR induction. UPR activation may contribute to breast cancer chemoresistance and interact with oestrogen response elements.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2009 Cancer Research UK. From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ |
Keywords: | breast cancer; unfolded protein response; stress response; GLUCOSE-REGULATED PROTEINS; CELLS; GRP78; EXPRESSION; RESISTANCE; ESTROGEN; STARVATION; INDUCTION; ETOPOSIDE; PATHWAY |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 13 Apr 2016 12:32 |
Last Modified: | 13 Apr 2016 12:32 |
Published Version: | http://dx.doi.org/10.1038/sj.bjc.6605365 |
Status: | Published |
Publisher: | Cancer Research UK |
Refereed: | Yes |
Identification Number: | 10.1038/sj.bjc.6605365 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:97448 |
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