1. Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development
- Author
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Christoph F. A. Vogel, Gwendal Lazennec, Sarah Y. Kado, Carla Dahlem, Yi He, Alejandro Castaneda, Yasuhiro Ishihara, Christian Vogeley, Andrea Rossi, Thomas Haarmann-Stemmann, Juliann Jugan, Hidetoshi Mori, Alexander D. Borowsky, Michele A. La Merrill, Colleen Sweeney, University of California [Davis] (UC Davis), University of California, and CNRS UMR9005
- Subjects
0301 basic medicine ,Time Factors ,Antigens, Polyomavirus Transforming ,Drug Resistance ,Apoptosis ,Inbred C57BL ,Cell Transformation ,Animals, Genetically Modified ,Mice ,0302 clinical medicine ,Receptors ,carcinogenicity ,Basic Helix-Loop-Helix Transcription Factors ,Tumor Cells, Cultured ,2.1 Biological and endogenous factors ,Immunology and Allergy ,Aetiology ,cyclooxygenase 2 ,Cancer ,Original Research ,Etoposide ,Mammary tumor ,AhRR ,Cultured ,Environmental exposure ,3. Good health ,Tumor Cells ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Aryl Hydrocarbon ,Medical Microbiology ,030220 oncology & carcinogenesis ,C/EBPβ ,MCF-7 Cells ,Female ,Signal Transduction ,lcsh:Immunologic diseases. Allergy ,Genetically modified mouse ,Immunology ,Genetically Modified ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Antineoplastic Agents ,Breast Neoplasms ,Biology ,03 medical and health sciences ,Breast cancer ,breast cancer ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Antigens ,Carcinogen ,Cell Proliferation ,Neoplastic ,AhR ,medicine.disease ,Aryl hydrocarbon receptor ,Mice, Inbred C57BL ,Repressor Proteins ,030104 developmental biology ,Gene Expression Regulation ,Receptors, Aryl Hydrocarbon ,inflammation ,Doxorubicin ,Drug Resistance, Neoplasm ,Cancer cell ,Cancer research ,biology.protein ,C/EBP beta ,Polyomavirus Transforming ,Neoplasm ,lcsh:RC581-607 - Abstract
Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to known human carcinogens including dioxins can lead to the promotion of breast cancer. While the repressor protein of the AhR (AhRR) blocks the canonical AhR pathway, the function of AhRR in the development of breast cancer is not well-known. In the current study we examined the impact of suppressing AhR activity using its dedicated repressor protein AhRR. AhRR is a putative tumor suppressor and is silenced in several cancer types, including breast, where its loss correlates with shorter patient survival. Using the AhRR transgenic mouse, we demonstrate that AhRR overexpression opposes AhR-driven and inflammation-induced growth of mammary tumors in two different murine models of breast cancer. These include a syngeneic model using E0771 mammary tumor cells as well as the Polyoma Middle T antigen (PyMT) transgenic model. Further AhRR overexpression or knockout of AhR in human breast cancer cells enhanced apoptosis induced by chemotherapeutics and inhibited the growth of mouse mammary tumor cells. This study provides the first in vivo evidence that AhRR suppresses mammary tumor development and suggests that strategies which lead to its functional restoration and expression may have therapeutic benefit.
- Published
- 2021