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The role of GRP78 in the intrinsic actions of IGFBPs -2 and -3 in breast cancer

Bristol Medical School

About the Project

GRP78, also known as BiP, is a member of the heat shock protein 70 family that functions as the main inducer of the ER stress pathway, named the unfolded protein response (UPR). High expression of GRP78 contributes to cancer cell survival, progression, and metastasis. Recent studies demonstrated that GRP78 acts as a binding partner for IGFBP-3 and we have preliminary data that it also binds to IGFBP-2. High levels of IGFBP-2 and -3 have been consistently associated with tumour progression and may therefore be promising potential therapeutic targets.

We have recently determined that with breast cancer cells in vitro the actions of IGFBPs -2 and -3 are switched when GRP78 expression is silenced. Using immunofluorescence and cell surface biotinylation, we showed that knock-down of GRP78 negated the entry of IGFBPs -2 and -3 into the cells. This project aims to determine the signalling pathways that underly the differential effects of these IGFBPs, that are dependent on GRP78. With tumour tissue samples, we also have preliminary data to suggest that the relative levels of the IGFBPs and GRP78 impact on patient survival.

We shall for example use cell culture, western immunoblotting, proteomics, PCR, phenotypic assays, such as proliferation, survival, migration, and invasion. We shall also perform in silico analysis to investigate if any traits, such as GRP-78, identified are causally associated with risk and development of cancer and overall survival. We shall use Mendelian randomization, developed at the University of Bristol, which employs genetic variants robustly associated with exposures of interest as instrumental variables to test and estimate the unconfounded and unbiased causal effect of those exposures with cancer. This will provide important information to support the identification of the most relevant potential drug targets to prevent metabolically induced metastases.

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