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Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. 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The human metabolite data collection and analysis, immunohistochemistry, and antibody validation performed by AW was supported by a grant from Breast Cancer UK (PO-180309) and by the University of Leeds School of Food Science and Nutrition. The British Endocrine Society provided an equipment award (NOV2016) allowing the development of the high throughput chemotherapy efflux assay. SAH, CS, and PL were supported with Leeds Doctoral Scholarships and School of Food Science and Nutrition consumables support. ERN was supported by the National Cancer Institute of the National Institutes of Health (R01CA234025).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Financial support"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}