The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis.

Abstract

BACKGROUND:

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. Aryl hydrocarbon receptor (AHR) ligands show promise as antimetastatic drugs for estrogen receptor (ER)-negative breast cancer.

METHODS:

Triple 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.

RESULTS:

We 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.

CONCLUSIONS:

AHR-active pharmaceuticals such as omeprazole that decrease breast cancer cell invasion and metastasis may have important clinical applications for late stage breast cancer chemotherapy.

• Authors: Un-Ho Jin, Syng-Ook Lee, Catherine Pfent, Stephen Safe
• Journal: BMC cancer (BMC Cancer) Vol. 14 Pg. 498 (Jul 09 2014) ISSN: 1471-2407 [Electronic] England
• PMID: 25011475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AHR protein, human
• Basic Helix-Loop-Helix Transcription Factors
• Receptors, Aryl Hydrocarbon
• Omeprazole

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (agonists)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, secondary)
• MCF-7 Cells
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Omeprazole (pharmacology)
• Receptors, Aryl Hydrocarbon (agonists)
• Triple Negative Breast Neoplasms (drug therapy, pathology)
• Xenograft Model Antitumor Assays