Liver × receptor ligands disrupt breast cancer cell proliferation through an E2F-mediated mechanism.

摘要: Introduction: Liver × receptors (LXRs) are members of the nuclear receptor family ligand-dependent transcription factors and have established functions as regulators cholesterol, glucose, fatty acid metabolism inflammatory responses. Published reports anti-proliferative effects synthetic LXR ligands on breast, prostate, ovarian, lung, skin, colorectal cancer cells suggest that LXRs potential targets in prevention treatment. Methods: To further determine identify their mechanisms action breast cells, we carried out microarray analysis gene expression four cell lines following treatments with ligand GW3965. Differentially expressed genes were subjected to ontology pathway analyses, profiles associations disease parameters outcomes examined clinical samples. Response E2F target validated by real-time PCR, posited role E2F2 proliferation was tested RNA interference experiments. Results: We observed line-specific transcriptional responses well a set common responsive genes. In set, upregulated tend function known metabolic whereas downregulated mostly include those which cycle regulation, DNA replication, other proliferation-related processes. Transcription factor binding site revealed an enrichment sequence motifs. Correspondingly, transcript levels Knockdown expression, similar treatment, resulted significant disruption estrogen positive proliferation. Ligand treatment also decreased cis-regulatory regions Hierarchical clustering patients based commonly ligand-responsive showed strong association these patient survival. Conclusions: Taken together, results indicate networks, including regulated members, critical for tumor biology progression merit consideration agents cancers.