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Interaction between GRP78 and IGFBP-3 affects tumourigenesis and prognosis in breast cancer patients

Zielinska, Hanna A.; Daly, Carl S.; Alghamdi, Ahmad; Bahl, Amit; Sohail, Muhammed; White, Paul; Holly, Jeff M. P.; Dean, Sarah R.; Perks, Claire M.

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Authors

Hanna A. Zielinska

Carl S. Daly

Ahmad Alghamdi

Amit Bahl

Muhammed Sohail

Paul White Paul.White@uwe.ac.uk
Professor in Applied Statistics

Jeff M. P. Holly

Sarah Dean Sarah4.Dean@uwe.ac.uk
Senior Lecturer in Biomedical Science

Claire M. Perks



Abstract

Insulin-like growth factor binding protein 3 (IGFBP-3) plays a key role in breast cancer progression and was recently shown to bind to the chaperone protein glucose-regulated protein 78 (GRP78); however, the clinical significance of this association remains poorly investigated. Here we report a direct correlation between the expression of GRP78 and IGFBP-3 in breast cancer cell lines and tumour sections. Kaplan–Meier survival plots revealed that patients with low GRP78 expression that are positive for IGFBP-3 had poorer survival rates than those with low IGFBP-3 levels, and we observed a similar trend in the publicly available METABRIC gene expression database. With breast cancer cells, in vitro IGFBP-3 enhanced induced apoptosis, however when GRP78 expression was silenced the actions of IGFBP-3 were switched from increasing to inhibiting ceramide (C2)-induced cell death and promoted cell invasion. Using immunofluorescence and cell surface biotinylation, we showed that knock-down of GRP78 negated the entry of IGFBP-3 into the cells. Together, our clinical and experimental results suggest that loss of GRP78 reduces IGFBP-3 entry into cells switching its actions to promote tumorigenesis and predicts a poor prognosis in breast cancer patients.

Journal Article Type Article
Acceptance Date Dec 15, 2020
Online Publication Date Dec 18, 2020
Publication Date Dec 18, 2020
Deposit Date Feb 14, 2021
Publicly Available Date Feb 18, 2021
Journal Cancers
Electronic ISSN 2072-6694
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 12
Issue 12
Article Number 3821
Pages 1-13
DOI https://doi.org/10.3390/cancers12123821
Keywords Cancer Research; Oncology; breast cancer prognosis; GRP78; IGFBP-3; metastasis
Public URL https://uwe-repository.worktribe.com/output/6972736

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