An Aryl Hydrocarbon Receptor-Mediated Amplification Loop That Enforces Cell Migration in ER-/PR-/Her2- Human Breast Cancer Cells
| Autor: | Kyongbum Lee, Israa Laklouk, Stefano Monti, Sara Manteiga, Carmen Sarita-Reyes, Amy Li, Ashley J. Parks, David H. Sherr, Olga Novikov, Zhongyan Wang, Esther Landesman, Elizabeth A. Stanford, Alejandra Ramirez-Cardenas, Daniel Gusenleitner |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Xanthurenates Kynurenine pathway Receptor ErbB-2 Endogeny Triple Negative Breast Neoplasms Ligands Models Biological 03 medical and health sciences chemistry.chemical_compound Cell Movement Cell Line Tumor Humans RNA Messenger Receptor Kynurenine Pharmacology Regulation of gene expression biology Gene Amplification Tryptophan Cell migration Articles respiratory system Aryl hydrocarbon receptor Immunohistochemistry Tryptophan Oxygenase Cell biology respiratory tract diseases Gene Expression Regulation Neoplastic 030104 developmental biology Biochemistry chemistry Receptors Aryl Hydrocarbon Receptors Estrogen Gene Knockdown Techniques Cancer cell biology.protein Molecular Medicine Female Receptors Progesterone |
| Zdroj: | Molecular Pharmacology |
| ISSN: | 1521-0111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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