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The liver x receptors (LXR) alpha and beta are ligand-responsive transcription factors that link homeostatic control of lipid metabolism with cancer pathophysiology and prognosis. LXR activity is elevated in triple negative breast cancer relative to other breast cancer subtypes, driving gene signatures associated with drug resistance and metastasis. The loci encoding LXRα and LXRβ produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Seven splice variants of LXRα or LXRβ were detected. Three have not been recorded previously and five were prognostic. High expression of full length LXRα was associated with shorter disease-free survival but splice variants harbouring truncations of the ligand binding domain were prognostic for improved survival. All LXRβ variants were associated with longer disease-free survival. Mechanistically, while full length LXRα positively correlated with target gene expression in primary samples, LXRβ was inversely correlated. We conclude that canonical LXRα function is an oncogenic driver of triple negative tumour pathophysiology that can be countered by high expression of truncated splice variants and/or full length LXRβ.HighlightsExpression of full length LXRα is associated with shorter disease-free survival of triple negative breast cancer patientsA systematic evaluation of cell lines and primary tumour samples indicates LXR splicing is extensive in breast cancerConfirmation of three new LXR splice variants at transcript and protein levelExpression of full length LXRβ or LXRα splice variants that harbour truncated ligand binding domains are associated with better prognosisExpression of LXR target genes is positively correlated with LXRα in relapsed patients and inversely correlated with LXRβ in survivors.

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.

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.

Interventions that alter cholesterol have differential impacts on hormone receptor positive- and negative-breast cancer risk and prognosis. This implies differential regulation or response to cholesterol within different breast cancer subtypes. We evaluated differences in side-chain hydroxycholesterol and liver X nuclear receptor signalling between Oestrogen Receptor (ER)-positive and ER-negative breast cancers and cell lines. Cell line models of ER-positive and ER-negative disease were treated with Liver X Receptor (LXR) ligands and transcriptional activity assessed using luciferase reporters, qPCR and MTT. Publicly available datasets were mined to identify differences between ER-negative and ER-positive tumours and siRNA was used to suppress candidate regulators. Compared to ER-positive breast cancer, ER-negative breast cancer cells were highly responsive to LXR agonists. In primary disease and cell lines LXRA expression was strongly correlated with its target genes in ER-negative but not ER-positive disease. Expression of LXR&rsquo, s corepressors (NCOR1, NCOR2 and LCOR) was significantly higher in ER-positive disease relative to ER-negative, and their knock-down equalized sensitivity to ligand between subtypes in reporter, gene expression and viability assays. Our data support further evaluation of dietary and pharmacological targeting of cholesterol metabolism as an adjunct to existing therapies for ER-negative and ER-positive breast cancer patients.

Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic colonization, indicating tumour suppressing and promoting roles. Phytosterols and phytostanols in plants, like cholesterol in mammals, are essential components of the plasma membrane and biochemical precursors, and in human cells can alter LXR transcriptional activity. Here, a panel of breast cancer cell lines were treated with four dietary plant sterols and a stanol, alone or in combination with oxysterols. LXR activation and repression were measured by gene expression and LXR-luciferase reporter assays. Oxysterols activated LXR in all cell lines, but surprisingly phytosterols failed to modulate LXR activity. However, phytosterols significantly inhibited the ability of oxysterols to drive LXR transcription. These data support a role for phytosterols in modulating cancer cell behaviour via LXR, and therefore suggest merit in accurate dietary recordings of these molecules in cancer patients during treatment and perhaps supplementation to benefit recovery.

Background Quail egg (QE) has been reported to possess an anti-allergic and anti-inflammatory activity. We have demonstrated that whole QE was able to attenuate the allergic symptoms in food allergy-induced EoE murine model, but whether QE albumen or QE yolk plays a more important role still remains unclear. Objective In this current study, we investigated the suppressive role of QE in mast cell degranulation and cytokine production of the effect phase response. Method A passive cutaneous anaphylaxis (PCA) mouse model was used to confirm the anti-allergic effect of QE. Besides, HMC-1 cell model was used to study its suppressive role in more detail. In this in vitro study, we divided QE into three groups: whole QE, QE albumen, and QE yolk. The effect of QE treatment on mast cell degranulation and intracellular calcium influx was investigated. Moreover, the effect of QE allergy- related mediators, genes, and proteins were also assessed by ELISA, RT-PCR, and western blotting. Results and discussion Our data showed that the extent of mast cell degranulation-mediated ear vascular permeability in IgE-mediated PCA mice treated with whole QE (17 mg/kg) was decreased significantly up to 43.31 ± 0.42% reduction. HMC-1 cell-based immunological assay in vitro indicated that QE, particularly its albumen, acted as a 'mast cell stabilizer'. Under the concentration of 70 μg/mL, QE albumen effectively suppressed the releases of β-hexosaminidase, histamine, and tryptase, as well as Th2 and pro-inflammatory cytokine production; reached 30 up to 50% reduction. Besides, QE albumen was also able to significantly modulate the upregulation of IL-10 up to 58.30 ± 5.9%. Interestingly, our data indicated that QE yolk still had a significant inhibitory effect on modulating Th2 cytokines in its highest concentration (100 μg/mL), while QE albumen showed no inhibitory effect. Western blot analysis showed QE albumen effectively down-regulated the expressions of calcium-related protein (TRPC1, Orai1, STIM1, PLC-γ and IP3R), facilitated the reduction of PAR-2 and induced the reduction of phosphorylation of JNK, IKKα, p50 and p65 protein expressions. Conclusion As confirmed by PCA and HMC-1 cell-based immunology assay, QE albumen and QE yolk may work together through exerting anti-allergy activity and can be used as a potential anti-allergic nutrient in the future.