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.

Comprehensive profiling of liver x receptor splicing in triple negative breast cancer reveals existence of novel splice variants that are prognostic for survival

“…To confirm if the protein bands were LXRa variants, we first performed siLXRa treatments in cell lines. Using previously validated [7] siRNA duplexes (Origene trisilencers) against LXRα and LXRβ we found that the protein bands predicted by size to be α1, α2, α3, a5, and b1 were all significantly reduced by targeted siRNA in all cell lines tested (all p<0.05; SF7). Note: a4 and b4 were not expressed in cell lines so could not be validated in this way.…”

“…We previously reported that LXRα expression is positively correlated to target gene expression in ER-negative patients who had relapsed and/or died due to their disease (Event patients) but not those who survive disease free (No Event patients) [7]. Here, we tested the hypothesis that differential LXR splice variant expression between cancers may contribute to disease aetiology via their ability to control expression of gene targets.…”

“…Here, we tested the hypothesis that differential LXR splice variant expression between cancers may contribute to disease aetiology via their ability to control expression of gene targets. LXR splice variant expression was tested for correlations with established LXR target genes, ABCA1 and ABCB1 [7]. Expression of both full-length isoforms (α1 and α4) positively correlated with expression of both ABCA1 or ABCB1, but interestingly only in Event patients (p<0.05 for all; Fig5).…”

“…It is The copyright holder for this preprint this version posted June 10, 2021. ; https://doi.org/10.1101/2021.06.09.445161 doi: bioRxiv preprint Thirty-eight frozen tumour samples were obtained with ethical approval from the Leeds Breast Research Tissue Bank (15/HY/0025 and LBTB_TAC_1/17). The clinicopathological features and selection criteria of these cohorts have been described previously [7,11,12,21] Thermo Fisher, UK, Cat. 11560636) and incubated in 37 o C, 5% CO2.…”

“…The liver x receptors (LXRα/NR1H3; LXRβ/NR1H2) are homeostatic regulators of cholesterol metabolism and as such have been suggested as potential therapeutic targets. LXRa activation by hydroxylated cholesterol (oxysterols) has been linked to poor survival by driving multi-drug resistance in TNBC patients [7], and increased metastasis in mouse models [8,9]. On the other hand, LXRb activation by histamine conjugated oxysterols such as dendrogenin A can induce lethal autophagy in breast cancer [10].…”