Journal
ONCOGENE
Volume 40, Issue 16, Pages 2872-2883Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-021-01720-w
Keywords
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Funding
- Breast Cancer Action [3T57/9R17-02]
- Breast Cancer UK [PO-180309]
- University of Leeds School of Food Science and Nutrition
- British Endocrine Society
- National Cancer Institute of the National Institutes of Health [R01CA234025]
- School of Food Science and Nutrition
- Leeds Doctoral Scholarships
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Triple negative breast cancer (TNBC) is difficult to treat due to lack of targeted therapies, with chemotherapy often failing in patients with high circulating cholesterol. The study reveals that LXR ligands can lead to chemotherapy resistance in TNBC, with LXRalpha and P-glycoprotein being markers of poor prognosis in patients with cancer recurrences. Targeting the LXRalpha:P-glycoprotein axis may offer new treatment options for TNBC patients who do not respond well to systemic chemotherapy.
Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. 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. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.
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