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      Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer

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          Abstract

          Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to chemicals including polycyclic aromatic hydrocarbons (PAHs) and polychlorinated dibenzo-p-dioxins (PCDDs) can lead to severe adverse health effects and increase the risk of breast cancer. This review considers several mechanisms which link the tumor promoting effects of environmental pollutants with the AhR signaling pathway, contributing to the development and progression of breast cancer. We explore AhR’s function in shaping the tumor microenvironment, modifying immune tolerance, and regulating cancer stemness, driving breast cancer chemoresistance and metastasis. The complexity of AhR, with evidence for both oncogenic and tumor suppressor roles is discussed. We propose that AhR functions as a “molecular bridge”, linking disproportionate toxin exposure and policies which underlie environmental injustice with tumor cell behaviors which drive poor patient outcomes.

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          Most cited references173

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          Understanding the tumor immune microenvironment (TIME) for effective therapy

          The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
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            Microenvironmental regulation of metastasis.

            Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.
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              Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.

              TGF-beta blockade significantly slows tumor growth through many mechanisms, including activation of CD8(+) T cells and macrophages. Here, we show that TGF-beta blockade also increases neutrophil-attracting chemokines, resulting in an influx of CD11b(+)/Ly6G(+) tumor-associated neutrophils (TANs) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of proinflammatory cytokines. Accordingly, following TGF-beta blockade, depletion of these neutrophils significantly blunts antitumor effects of treatment and reduces CD8(+) T cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8(+) T cells intratumorally. Together, these data suggest that TGF-beta within the tumor microenvironment induces a population of TAN with a protumor phenotype. TGF-beta blockade results in the recruitment and activation of TANs with an antitumor phenotype.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                15 December 2022
                2022
                : 13
                : 1095289
                Affiliations
                [1] 1 Department of Biochemistry and Molecular Medicine , School of Medicine , University of California Davis , Sacramento, CA, United States
                [2] 2 Centre National de la Recherche Scientifique , SYS2DIAG-ALCEN , Cap Delta , Montpellier, France
                [3] 3 Center for Health and the Environment , University of California Davis , Davis, CA, United States
                [4] 4 Department of Environmental Toxicology , University of California Davis , Davis, CA, United States
                Author notes

                Edited by: Amir Shadboorestan, Tarbiat Modares University, Iran

                Reviewed by: Rridha Oueslati, University Carthage—Sciences Faculty of Bizerte, Tunisia

                David H. Sherr, Boston University, United States

                *Correspondence: Christoph F. A. Vogel, cfvogel@ 123456ucdavis.edu

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

                Article
                1095289
                10.3389/fphar.2022.1095289
                9797527
                36588678
                f5b9df08-18d1-42e7-a4ca-0026db50fd24
                Copyright © 2022 Sweeney, Lazennec and Vogel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 11 November 2022
                : 05 December 2022
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                ahr,breast cancer,air pollution,particulate matter,environmental injustice,macrophages,tumor microenvironment,tumor promotion

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