Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer.
Animals
Benzoates
/ pharmacology
Benzylamines
/ pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
Epirubicin
/ pharmacology
Female
Gene Expression
Humans
Hydroxycholesterols
/ metabolism
Liver X Receptors
/ agonists
Mammary Neoplasms, Experimental
/ drug therapy
Mice
Mice, Inbred BALB C
Triple Negative Breast Neoplasms
/ drug therapy
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
06
08
2020
accepted:
18
02
2021
revised:
15
02
2021
pubmed:
21
3
2021
medline:
3
11
2021
entrez:
20
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33742124
doi: 10.1038/s41388-021-01720-w
pii: 10.1038/s41388-021-01720-w
pmc: PMC8062267
mid: NIHMS1675462
doi:
Substances chimiques
Benzoates
0
Benzylamines
0
GW 3965
0
Hydroxycholesterols
0
Liver X Receptors
0
NR1H3 protein, human
0
Epirubicin
3Z8479ZZ5X
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2872-2883Subventions
Organisme : NCI NIH HHS
ID : R01 CA234025
Pays : United States
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