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.

Characterization and prognostic value of LXR splice variants in triple-negative breast cancer

“…To confirm if the protein bands were LXRa variants, we first performed siLXRa treatments in cell lines. Using previously validated (Hutchinson et al, 2021) siRNA duplexes (Origene trisilencers) against LXRa and LXRb, we found that the protein bands predicted by size to be a1, a2, a3, a5, and b1 were all significantly reduced by targeted siRNA in all cell lines tested (all p < 0.05; Figure S10). Note that a4 and b4 were not expressed in cell lines and so could not be validated in this way.…”

“…We previously reported that LXRa 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 (Hutchinson et al, 2021). Here, we tested the hypothesis that differential LXR splice variant expression between cancers may contribute to disease etiology via their ability to control expression of gene targets.…”

“…The liver x receptors (LXRa/NR1H3; LXRb/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 patients with TNBC (Hutchinson et al, 2021) and increased metastasis in mouse models (Baek et al, 2017;Nelson et al, 2013). On the other hand, LXRb activation by histamine conjugated oxysterols such as dendrogenin A can induce lethal autophagy in BCa (Poirot and Silvente-Poirot, 2018).…”

The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer

“…In contrast, activation of LXR by LXR agonist inhibited breast cancer cell proliferation in vitro [51]. Interestingly, Hutchinson et al reported that activation of LXR by LXR antagonist contributes to resistance of triple negative breast cancer to epirubicin in vivo [52]. Possibly, the efficacy of specific agents depends on in vitro vs. in vivo methods, tumor type or genotype, or the specific regimen or drug combination evaluated.…”

Overlap between nutrient metabolism and chemotherapy detoxification in triple negative breast cancer

“…Leeds teaching Hospitals NHS Trust, Leeds, UK Detoxification and nutrient metabolism are connected in healthy tissues to prevent toxic accumulation of metabolic intermediates and end-products (1) . These pathways also enhance processing of xenobiotics such as anti-cancer drugs (2) . Resistance to anti-cancer drugs remains a major barrier to successful treatment of many cancer types, yet clinical tools that predict which treatment regimen would be most effective at individual patient level remain underdeveloped.…”