Abstract
IntroductionLiver × receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors and have established functions as regulators of cholesterol, glucose, and fatty acid metabolism and inflammatory responses. Published reports of anti-proliferative effects of synthetic LXR ligands on breast, prostate, ovarian, lung, skin, and colorectal cancer cells suggest that LXRs are potential targets in cancer prevention and treatment.MethodsTo further determine the effects of LXR ligands and identify their potential mechanisms of action in breast cancer cells, we carried out microarray analysis of gene expression in four breast cancer cell lines following treatments with the synthetic LXR ligand GW3965. Differentially expressed genes were further subjected to gene ontology and pathway analyses, and their expression profiles and associations with disease parameters and outcomes were examined in clinical samples. Response of E2F target genes were validated by real-time PCR, and the posited role of E2F2 in breast cancer cell proliferation was tested by RNA interference experiments.ResultsWe observed cell line-specific transcriptional responses as well as a set of common responsive genes. In the common responsive gene set, upregulated genes tend to function in the known metabolic effects of LXR ligands and LXRs whereas the downregulated genes mostly include those which function in cell cycle regulation, DNA replication, and other cell proliferation-related processes. Transcription factor binding site analysis of the downregulated genes revealed an enrichment of E2F binding site sequence motifs. Correspondingly, E2F2 transcript levels are downregulated following LXR ligand treatment. Knockdown of E2F2 expression, similar to LXR ligand treatment, resulted in a significant disruption of estrogen receptor positive breast cancer cell proliferation. Ligand treatment also decreased E2F2 binding to cis-regulatory regions of target genes. Hierarchical clustering of breast cancer patients based on the expression profiles of the commonly downregulated LXR ligand-responsive genes showed a strong association of these genes with patient survival.ConclusionsTaken together, these results indicate that LXR ligands target gene networks, including those regulated by E2F family members, are critical for tumor biology and disease progression and merit further consideration as potential agents in the prevention and treatment of breast cancers.
Highlights
Liver × receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors and have established functions as regulators of cholesterol, glucose, and fatty acid metabolism and inflammatory responses
To further determine the impact of the downregulation of estrogen receptor (ER) expression on the changes in gene expression following ligand treatment, we cross-referenced the 193 common ligand-responsive genes in the two ER+ cells lines and compared them to a list of 938 estrogen-responsive genes identified in previously published studies [26,27,28,29]
In ERbreast cancer cells, 603 genes were responsive to ligand treatment in SK-BR-3 cells, and 926 genes were responsive in the triple-negative MDA-MB-231 cells
Summary
Liver × receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors and have established functions as regulators of cholesterol, glucose, and fatty acid metabolism and inflammatory responses. Advances in breast cancer therapy are facilitated by molecular characterizations of tumors and tumor subtypes. Breast tumors that express estrogen receptor (ER-positive, ER+) and progesterone receptor (PR-positive, PR+) and are dependent on the female sex hormone estrogen for growth and proliferation are treated by drugs that target ER either directly (tamoxifen, raloxifene, fulvestrant) or indirectly (letrozole, anastrozole, exemestane) by disrupting estrogen production [1,2]. Tumors that overexpress human epidermal growth factor receptor 2 (HER2/ErbB-2/neu+) on cell surfaces are targeted by monoclonal antibodies (trastuzumab) or tyrosine kinase inhibitors (lapatinib), which block receptor activation and tumor cell proliferation [3]. Improvements of current breast cancer therapeutics and development of new ones necessitate the discovery and characterization of novel target mechanisms and targeting agents
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