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.

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