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Article: AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer

TitleAhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer
Authors
KeywordsAmphiregulin
Aryl hydrocarbon receptor
Reactive oxygen species
Triple-negative breast cancer
Tumor-associated macrophages
Issue Date2019
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2019, v. 116, n. 9, p. 3604-3613 How to Cite?
Abstract© 2019 National Academy of Sciences. All Rights Reserved. Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.
Persistent Identifierhttp://hdl.handle.net/10722/292105
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKubli, Shawn P.-
dc.contributor.authorBassi, Christian-
dc.contributor.authorRoux, Cecilia-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorGöbl, Christoph-
dc.contributor.authorZhou, Wenjing-
dc.contributor.authorJafari, Soode Moghadas-
dc.contributor.authorSnow, Bryan-
dc.contributor.authorJones, Lisa-
dc.contributor.authorPalomero, Luis-
dc.contributor.authorThu, Kelsie L.-
dc.contributor.authorCassetta, Luca-
dc.contributor.authorSoong, Daniel-
dc.contributor.authorBerger, Thorsten-
dc.contributor.authorRamachandran, Parameswaran-
dc.contributor.authorBaniasadi, Shakiba P.-
dc.contributor.authorDuncan, Gordon-
dc.contributor.authorLindzen, Moshit-
dc.contributor.authorYarden, Yosef-
dc.contributor.authorHerranz, Carmen-
dc.contributor.authorLazaro, Conxi-
dc.contributor.authorChu, Mandy F.-
dc.contributor.authorHaight, Jillian-
dc.contributor.authorTinto, Paul-
dc.contributor.authorSilvester, Jennifer-
dc.contributor.authorCescon, David W.-
dc.contributor.authorPetit, Anna-
dc.contributor.authorPettersson, Sven-
dc.contributor.authorPollard, Jeffrey W.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorPujana, Miguel A.-
dc.contributor.authorCappello, Paola-
dc.contributor.authorGorrini, Chiara-
dc.date.accessioned2020-11-17T14:55:46Z-
dc.date.available2020-11-17T14:55:46Z-
dc.date.issued2019-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2019, v. 116, n. 9, p. 3604-3613-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/292105-
dc.description.abstract© 2019 National Academy of Sciences. All Rights Reserved. Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectAmphiregulin-
dc.subjectAryl hydrocarbon receptor-
dc.subjectReactive oxygen species-
dc.subjectTriple-negative breast cancer-
dc.subjectTumor-associated macrophages-
dc.titleAhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1815126116-
dc.identifier.pmid30733286-
dc.identifier.pmcidPMC6397541-
dc.identifier.scopuseid_2-s2.0-85062016645-
dc.identifier.volume116-
dc.identifier.issue9-
dc.identifier.spage3604-
dc.identifier.epage3613-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000459694400045-
dc.identifier.issnl0027-8424-

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