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

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 enhances 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 29
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.
Original languageEnglish
Article number3821
Number of pages13
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - 18 Dec 2020

Structured keywords

  • ICEP

Keywords

  • Breast cancer prognosis
  • GRP78
  • IGFBP-3
  • metastasis

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