title: The aryl hydrocarbon receptor (AhR) mediates resistance to apoptosis induced in breast cancer cells.
abstract: The aryl hydrocarbon receptor (AhR) is well known as a ligand binding transcription factor regulating various biological effects. Previously we have shown that long-term exposure to estrogen in breast cancer cells caused not only down regulation of estrogen receptor (ER) but also overexpression of AhR. The AhR interacts with several cell signaling pathways associated with induction of tyrosine kinases, cytokines and growth factors which may support the survival roles of AhR escaping from apoptosis elicited by a variety of apoptosis inducing agents in breast cancer. In this study, we studied the anti-apoptotic role of AhR in different breast cancer cells when apoptosis was induced by exposure to UV light and chemotherapeutic agents. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in AhR overexpressing breast cancer cells effectively suppressed the apoptotic response induced by UV-irradiation, doxorubicin, lapatinib and paclitaxel. The anti-apoptotic response of TCDD was uniformly antagonized by the treatment with 3'methoxy-4'nitroflavone (MNF), a specific antagonist of AhR. TCDD's survival action of apoptosis was accompanied with the induction of well-known inflammatory genes, such as cyclooxygenase-2 (COX-2) and NF-κB subunit RelB. Moreover, TCDD increased the activity of the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO), which metabolizes tryptophan to kynurenine (Kyn) and mediates tumor immunity. Kyn also acts as an AhR ligand like TCDD, and kyn induced an anti-apoptotic response in breast cancer cells. Accordingly, our present study suggests that AhR plays a pivotal role in the development of breast cancer via the suppression of apoptosis, and provides an idea that the use of AhR antagonists with chemotherapeutic agents may effectively synergize the elimination of breast cancer cells.
authors.affiliation: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Kanae
authors.initials: K
authors.lastname: Bekki
authors.affiliation: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ito
authors.affiliation: Cancer Research Center, Basic Science Research, Medical School, University of California, Davis, CA 95817, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Sweeney
authors.affiliation: Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haarmann-Stemmann
authors.affiliation: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Environmental Toxicology, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Fumio
authors.initials: F
authors.lastname: Matsumura
authors.affiliation: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA; Department of Environmental Toxicology, University of California Davis, One Shields Avenue, Davis, CA 95616, USA. Electronic address: cfvogel@ucdavis.edu.
authors.forename: Christoph F A
authors.initials: CF
authors.lastname: Vogel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007737:Kynurenine / Q000494:pharmacology; D000077341:Lapatinib; D017239:Paclitaxel / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; C576710:IDO1 protein, human; C576711:IDO2 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000072317:Polychlorinated Dibenzodioxins; D011799:Quinazolines; C497593:RELB protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D000077341:Lapatinib; D051841:Transcription Factor RelB; D007737:Kynurenine; D004317:Doxorubicin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017239:Paclitaxel
keywords: AhR; Apoptosis; Breast cancer; IDO; NF-κB; TCDD