Functional significance of Tumor Protein D52 amplification and overexpression in cancer

Abstract

Tumor Protein D52 (TPD52) is an oncogene whose overexpression has been demonstrated in tumours of diverse cellular origins and associated with poor prognosis. Although the breadth and clinical significance of TPD52 overexpression in cancer is now well-established, there remains a long-standing deficit in our understanding of its functional significance. TPD52 is located on the frequently gained chromosome band 8q21, where we propose that it is an amplification target. We analysed TPD52 amplification in 995 cancer cell lines and then investigated whether this was broadly associated with altered lipid phenotypes in a selection of these cell lines. We demonstrated a significant positive association between TPD52 expression and lipid droplet staining, with increased lipid droplet number and size upon exogenous TPD52 overexpression in MDAMB231 cells. Furthermore, TPD52 interacted directly with the lipid droplet-associated proteins, adipophilin and TIP47. This suggests a role for TPD52 in intracellular lipid storage, which is important to cancer cells since their rapid proliferation is contingent upon having sufficient lipid for membrane synthesis. We therefore hypothesised that TPD52 overexpression could be applied clinically as a predictive marker for cancers likely to respond to drugs that interfere with lipid pathways. We performed predictive modelling using pharmacogenomic datasets to investigate for the first time whether TPD52 amplification and/or overexpression was associated with altered sensitivity to different drugs. These analyses identified several compounds for future validation, of which the lipid-relevant drugs fatostatin and brefeldin A were pursued in in vitro studies. Collectively, the findings presented in this thesis represent a significant step forward in our understanding of how TPD52 amplification and/or overexpression may contribute to the development of cancer at a molecular level, and how this could be applied to improve cancer treatment.