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’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.

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.

The present pharmacotherapy for eosinophilic esophagitis (EoE) fundamentally depend on inhaled corticosteroids. Despite the fact that oral intake of topical steroids can be successful in restricting EoE-related inflammation, there are concerns with respect to the long term utilization of steroids, especially in kids. In the current research, we assess the effect of quail egg, which is reportedly a known serine protease inhibitor, on symptomatology and immune responses in a peanut-sensitized mouse model of food allergy induced EoE. Daily oral treatment with quail egg attenuated mice symptomatology and immune response. Treatment with quail egg inhibited antigen-prompted increments in mouse tryptase and eosinophil cationic protein (ECP) in serum and eosinophil in inflamed tissues like oesophagus, lung, and digestive system. Quail egg treatment resulted in decreased antibody specific IgE and IgG1 and a variety of inflammatory genes that were abnormally expressed in EoE. Other effects included increased IL-10, decreased PAR-2 activation and NF-kB p65 in inflamed tissues. Our results suggest that quail egg treatment may have therapeutic potential in attenuating the symptoms of food allergy induced EoE like disease through regulating PAR-2 downstream pathway by blocking the activation of the transcription factor NF-kB p65 activity.

BackgroundQuail 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.ObjectiveIn this current study, we investigated the suppressive role of QE in mast cell degranulation and cytokine production of the effect phase response.MethodA 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 discussionOur 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.ConclusionAs 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.