Abstract
BackgroundPatients with ER-negative breast tumors are among the most difficult to treat and exhibit low survival rates due, in part, to metastasis from the breast to various distal sites. Aryl hydrocarbon receptor (AHR) ligands show promise as antimetastatic drugs for estrogen receptor (ER)-negative breast cancer.MethodsTriple negative MDA-MB-231 breast cancer cells were treated with eight AHR-active pharmaceuticals including 4-hydroxtamoxifen, flutamide leflunomide, mexiletine, nimodipine, omeprazole, sulindac and tranilast, and the effects of these compounds on cell proliferation (MTT assay) and cell migration (Boyden chamber assay) were examined. The role of the AHR in mediating inhibition of MDA-MB-231 cell invasion was investigated by RNA interference (RNAi) and knockdown of AHR or cotreatment with AHR agonists. Lung metastasis of MDA-MB-231 cells was evaluated in mice administered cells by tail vein injection and prometastatic gene expression was examined by immunohistochemistry.ResultsWe showed that only the proton pump inhibitor omeprazole decreased MDA-MB-231 breast cancer cell invasion in vitro. Omeprazole also significantly decreased MDA-MB-231 cancer cell metastasis to the lung in a mouse model (tail vein injection), and in vitro studies showed that omeprazole decreased expression of at least two prometastatic genes, namely matrix metalloproteinase-9 (MMP-9) and C-X-C chemokine receptor 4 (CXCR4). Results of RNA interference studies confirmed that omeprazole-mediated downregulation of CXCR4 (but not MMP-9) was AHR-dependent. Chromatin immunoprecipitation assays demonstrated that omeprazole recruited the AHR to regions in the CXCR4 promoter that contain dioxin response elements (DREs) and this was accompanied by the loss of pol II on the promoter and decreased expression of CXCR4.ConclusionsAHR-active pharmaceuticals such as omeprazole that decrease breast cancer cell invasion and metastasis may have important clinical applications for late stage breast cancer chemotherapy.
Highlights
Patients with estrogen receptor (ER)-negative breast tumors are among the most difficult to treat and exhibit low survival rates due, in part, to metastasis from the breast to various distal sites
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that was first discovered as an intracellular protein that bound with high affinity to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [1]
Omeprazole inhibits MDA-MB-231 cell invasion Table 1 and Additional file 1: Figure S1, Additional file 2: Figure S2 and Additional file 3: Figure S3 show that the eight Aryl hydrocarbon receptor (AHR)-active pharmaceuticals differentially activated cytochrome P4501A1 (CYP1A1) and cytochrome P4501B1 (CYP1B1) mRNA levels in MDA-MB-231 cells, and only 4-hydroxytamoxifen induced > 50% of the maximal response for both genes compared to 10 nM TCDD (100% response)
Summary
Patients with ER-negative breast tumors are among the most difficult to treat and exhibit low survival rates due, in part, to metastasis from the breast to various distal sites. The important role of the AHR and effects of AHR agonists or antagonists have been documented for various inflammatory conditions, stem cell stability and expansion, autoimmune diseases, and several different cancers and clearly demonstrate that this receptor is an important drug target [8,9,10,11,12,13,14,15] Research in this laboratory initially focused on the molecular mechanisms of inhibitory AHR-estrogen receptor (ER) crosstalk and development of selective AHR modulators (SAhRMs) for treatment of ER-positive breast cancer [16,17]. Selective receptor modulators are commonly observed for nuclear receptors such as the estrogen receptor (ER) and selective ER modulators have been extensively characterized for treatment of ER-positive breast cancer [28]
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