Oxysterol-LXR signalling in the triple negative breast cancer microenvironment

Triple negative breast cancers (TNBCs) are difficult to treat successfully due to the lack of targeted therapies. Instead, cytotoxic chemotherapy and radiotherapy are the most efficient treatments available. A common issue with chemotherapy is the development of multi-drug resistance in tumours, reducing the long-term efficacy of treatments. Studies have shown that elevated circulating cholesterol in TNBC patients associates with an increased risk of treatment failure. Liver x receptors (LXRs) are transcription factors activated by the cholesterol derivates, oxysterols. Their primary function is the regulation of cholesterol homeostasis but they also regulate expression of chemotherapy resistance protein, P-glycoprotein (Pgp), in non-cancer tissue. Previous work from the Thorne Lab has demonstrated that oxysterol-LXR signalling can induce Pgp expression in TNBC cells and subsequently enhance resistance to chemotherapy. My first aim was to demonstrate whether intratumour oxysterol content and the proteins responsible for their production correlated with Pgp expression in TNBC tumours, finding this to be true. As oxysterols can be sourced from a variety of cells in the tumour microenvironment (TME), I then investigated whether the fibroblasts of the TME contribute to LXR-mediated upregulation of epithelial Pgp expression. Here, cancer-associated fibroblasts (CAFs) were shown to be potent activators of LXR signalling in epithelial cells through in silico, in vitro and in vivo work in TNBC. CAFs were also shown to upregulate epithelial Pgp expression. Finally, the role of cholesterol esterification was also investigated as this can reduce intratumour oxysterol levels. To achieve this, I performed a meta-analysis that demonstrated how cholesterol esterification enhanced cancer progression through many mechanisms, one of which being through increased intratumour oxysterol content. In summary, LXR ligands and the enzymes that produce them positively associate with Pgp in TNBC tumours. Furthermore, CAFs are able to secrete oxysterols that activate LXR and induce expression of Pgp in epithelial cells. Finally, I have demonstrated that other cholesterol modifications, such as esterification also influence cancer progression.