Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer.

Abstract

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.

• Authors: Samantha A Hutchinson, Alex Websdale, Giorgia Cioccoloni, Hanne Røberg-Larsen, Priscilia Lianto, Baek Kim, Ailsa Rose, Chrysa Soteriou, Arindam Pramanik, Laura M Wastall, Bethany J Williams, Madeline A Henn, Joy J Chen, Liqian Ma, J Bernadette Moore, Erik Nelson, Thomas A Hughes, James L Thorne
• Journal: Oncogene (Oncogene) Vol. 40 Issue 16 Pg. 2872-2883 (04 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 33742124 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzoates
• Benzylamines
• GW 3965
• Hydroxycholesterols
• Liver X Receptors
• NR1H3 protein, human
• Epirubicin

Topics

• Animals
• Benzoates (pharmacology)
• Benzylamines (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Epirubicin (pharmacology)
• Female
• Gene Expression
• Humans
• Hydroxycholesterols (metabolism)
• Liver X Receptors (agonists, metabolism)
• Mammary Neoplasms, Experimental (drug therapy, genetics, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Triple Negative Breast Neoplasms (drug therapy, genetics, metabolism, pathology)