Investigating LXR as a therapeutic target in triple negative breast cancer.

The development of hormone therapies, such as tamoxifen, have substantially improved breast cancer outcomes for hormone receptor positive breast cancers. A subtype of breast cancers known as the triple negative breast cancers (TNBC) however, cannot benefit from these therapies due to their lack of receptors or overexpression of HER2 (ER-/PR-/HER2-). The triple negative subtype is associated with poorer prognosis and earlier relapse; novel therapies are urgently required for this cancer of unmet clinical need. The liver X receptor (LXR) is a ligand induced transcription factor with essential roles in cholesterol metabolism. LXRα and its binding partner RXRβ were found to be expressed at significantly higher levels in triple negative breast cancers relative to ER-positive breast cancers. I hypothesised that LXRα activity was altered between breast cancer subtypes and may influence chemotherapy efficacy. Enhanced LXRα response to ligand was identified in the TNBC subtype relative to the Luminal A subtype. Furthermore, LXRα was identified as a mediator of chemotherapy resistance through the control of the p-glycoprotein/ABCB1 in TNBC. I further hypothesised that the p-glycoprotein/ABCB1 may be targetable through phytosterol treatments which were shown to antagonise oxysterol-induced LXRα activity and expression of its targets which, we have been shown to include p-gp/ABCB1. In summary, I have identified a novel LXRα target gene (p-gp/ABCB1) in TNBC which confers chemotherapy resistance through enhanced export of the chemotherapy drug epirubicin. I have also established a mechanism to impair the oxysterol:LXRα axis through phytosterol treatment. The data presented here may have important implications to aid better treatment plans for patients undergoing chemotherapy treatment. It may also help identify individuals at risk of therapy failure.