Hormones and Cancer Division Growth Research Laboratory
Lab head: Robert Baxter
Location: Kolling Institute of Medical Research, Royal North Shore Hospital
Lab members: R Baxter (Lab Head), S Firth (Honorary Associate), J Martin (Senior Research Fellow), C Scott (Senior Research Fellow), L Chung (Research Fellow), Z Lin (Research Fellow), L Phillips (Technical Officer), H de Silva (Research Assistant), T Scully (PhD student), M Chua (MSc student)
Funding: NSW Cancer Council, Cancer Institute NSW
Research approach equipment: http://www.kolling.usyd.edu.au/core-facilities/index.php
IGFBP-3 promotes solid tumour cell survival in adverse microenvironments
Primary supervisor: Sue Firth
Background: Elevated expression of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) in tumour tissue has been associated with the stimulation of breast cancer. Although IGFBP‑3 is best known for its ability to control the bioavailability of the potent mitogenic and anti-apoptotic IGF peptides, we have shown that IGFBP-3 stimulates breast cancer independently of IGFs, via largely unknown mechanisms. In an exciting discovery, we found that IGFBP-3 interacts with GRP78, an ER resident chaperone that also, (1) acts as the master regulator of the ER stress response (known as the Unfolded Protein Response or UPR), (2) inhibits proapoptotic molecules localised to the ER and (3) is required for the initiation of pro-survival autophagic nutrient recycling. Of note, each of these GRP78 functions enhances the survival of solid tumour cells exposed to adverse microenvironments. Such stressful conditions frequently occur in vivo due to a shortage of oxygen and/or nutrients. Intriguingly, IGFBP-3 also confers a survival advantage to cells challenged by these same adverse microenvironments. The aim of this project is to determine whether IGFBP-3 stimulates survival and cancer progression via its interaction with GRP78.
Methods: The experimental system will compare breast cancer cell lines that express wildtype IGFBP-3 versus those that express an IGFBP-3 mutant deficient for the GRP78 interaction. The Honours candidate will have the opportunity to learn a wide range of cell biology and molecular biology techniques, including assays for proliferation, apoptosis and autophagy, as well as Western blots, immunofluorescence microscopy and quantitative RT-PCR. It is expected that the successful application of these techniques will provide confirmation that IGFBP-3 enhances specific GRP78 functions and thereby promotes the survival of cancer cells growing in adverse microenvironments.
Keywords: Cancer, breast tumour, Cell biology