The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy.

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the relatively non-toxic selective aryl hydrocarbon receptor (AhR) modulator 6-methyl-1,3,8-trichlorodibenzo-furan (MCDF) induced CYP1A1-dependent ethoxyresorufin O-deethylase activity and inhibited proliferation of seven estrogen receptor (ER) negative breast cancer cell lines. MCDF, TCDD and structurally related 2,3,7,8-tetrachlorodibenzofuran, 1,2,3,7,8-pentachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3',4,4',5-pentachlorobiphenyl induced CYP1A1 and inhibited proliferation of BT-474 and MDA-MB-468 cells. In BT474 and MDA-MB-468 cells transfected with a small inhibitory RNA for the AhR, the antiproliferative activity of the chlorinated aromatic compounds was reversed, whereas for MCDF, only partial reversal was observed, suggesting that this compound acts through both AhR-dependent and AhR-independent pathways in these two cell lines. MCDF also inhibited tumor growth in athymic nude mice in which MDA-MB-468 cells were injected directly into the mammary fat pad. These results suggest that the AhR is a potential drug target for treatment of ER-negative breast cancer.

• Authors: Shu Zhang, Ping Lei, Xinyi Liu, Xiangrong Li, Kelcey Walker, Leela Kotha, Craig Rowlands, Stephen Safe
• Journal: Endocrine-related cancer (Endocr Relat Cancer) Vol. 16 Issue 3 Pg. 835-44 (Sep 2009) ISSN: 1479-6821 [Electronic] England
• PMID: 19447902 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzofurans
• Carrier Proteins
• Polychlorinated Dibenzodioxins
• RNA, Small Interfering
• Receptors, Aryl Hydrocarbon
• Receptors, Estrogen
• estrophilin
• 6-methyl-1,3,8-trichlorodibenzofuran

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Benzofurans (pharmacology)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Carrier Proteins (genetics, metabolism)
• Cell Proliferation (drug effects)
• Drug Delivery Systems (methods)
• Female
• Humans
• Mice
• Mice, Nude
• Polychlorinated Dibenzodioxins (pharmacology)
• RNA, Small Interfering (pharmacology, therapeutic use)
• Receptors, Aryl Hydrocarbon (antagonists & inhibitors, physiology)
• Receptors, Estrogen (genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays