title: An Aryl Hydrocarbon Receptor-Mediated Amplification Loop That Enforces Cell Migration in ER-/PR-/Her2- Human Breast Cancer Cells.
abstract: The endogenous ligand-activated aryl hydrocarbon receptor (AHR) plays an important role in numerous biologic processes. As the known number of AHR-mediated processes grows, so too does the importance of determining what endogenous AHR ligands are produced, how their production is regulated, and what biologic consequences ensue. Consequently, our studies were designed primarily to determine whether ER-/PR-/Her2-breast cancer cells have the potential to produce endogenous AHR ligands and, if so, how production of these ligands is controlled. We postulated that: 1) malignant cells produce tryptophan-derived AHR ligand(s) through the kynurenine pathway; 2) these metabolites have the potential to drive AHR-dependent breast cancer migration; 3) the AHR controls expression of a rate-limiting kynurenine pathway enzyme(s) in a closed amplification loop; and 4) environmental AHR ligands mimic the effects of endogenous ligands. Data presented in this work indicate that primary human breast cancers, and their metastases, express high levels of AHR and tryptophan-2,3-dioxygenase (TDO); representative ER-/PR-/Her2-cell lines express TDO and produce sufficient intracellular kynurenine and xanthurenic acid concentrations to chronically activate the AHR. TDO overexpression, or excess kynurenine or xanthurenic acid, accelerates migration in an AHR-dependent fashion. Environmental AHR ligands 2,3,7,8-tetrachlorodibenzo[p]dioxin and benzo[a]pyrene mimic this effect. AHR knockdown or inhibition significantly reduces TDO2 expression. These studies identify, for the first time, a positive amplification loop in which AHR-dependent TDO2 expression contributes to endogenous AHR ligand production. The net biologic effect of AHR activation by endogenous ligands, which can be mimicked by environmental ligands, is an increase in tumor cell migration, a measure of tumor aggressiveness.
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Olga
authors: O
authors: Novikov
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Zhongyan
authors: Z
authors: Wang
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Elizabeth A
authors: EA
authors: Stanford
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Ashley J
authors: AJ
authors: Parks
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Alejandra
authors: A
authors: Ramirez-Cardenas
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Esther
authors: E
authors: Landesman
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Israa
authors: I
authors: Laklouk
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Carmen
authors: C
authors: Sarita-Reyes
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Daniel
authors: D
authors: Gusenleitner
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Amy
authors: A
authors: Li
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Stefano
authors: S
authors: Monti
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Sara
authors: S
authors: Manteiga
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.).
authors: Kyongbum
authors: K
authors: Lee
authors: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.) dsherr@bu.edu.
authors: David H
authors: DH
authors: Sherr
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D007737:Kynurenine / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism; D014977:Xanthurenates / Q000378:metabolism
chemical_list: D007737:Kynurenine; D008024:Ligands; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D014977:Xanthurenates; C028330:xanthurenic acid; C508053:ERBB2 protein, human