PMID- 30733286 OWN - NLM STAT- MEDLINE DCOM- 20190502 LR - 20220129 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 116 IP - 9 DP - 2019 Feb 26 TI - AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer. PG - 3604-3613 LID - 10.1073/pnas.1815126116 [doi] AB - 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. FAU - Kubli, Shawn P AU - Kubli SP AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. AD - Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. FAU - Bassi, Christian AU - Bassi C AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Roux, Cecilia AU - Roux C AD - Molecular Biotechnology Center, University of Turin, 10126 Turin, Italy. FAU - Wakeham, Andrew AU - Wakeham A AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Gobl, Christoph AU - Gobl C AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Zhou, Wenjing AU - Zhou W AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Jafari, Soode Moghadas AU - Jafari SM AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Snow, Bryan AU - Snow B AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Jones, Lisa AU - Jones L AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Palomero, Luis AU - Palomero L AD - Breast Cancer and Systems Biology Laboratory, Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research, L'Hospitalet del Llobregat, 08908 Barcelona, Spain. FAU - Thu, Kelsie L AU - Thu KL AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Cassetta, Luca AU - Cassetta L AD - Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom. FAU - Soong, Daniel AU - Soong D AD - Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom. FAU - Berger, Thorsten AU - Berger T AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Ramachandran, Parameswaran AU - Ramachandran P AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Baniasadi, Shakiba P AU - Baniasadi SP AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Duncan, Gordon AU - Duncan G AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Lindzen, Moshit AU - Lindzen M AD - Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel. FAU - Yarden, Yosef AU - Yarden Y AD - Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel. FAU - Herranz, Carmen AU - Herranz C AD - Breast Cancer and Systems Biology Laboratory, Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research, L'Hospitalet del Llobregat, 08908 Barcelona, Spain. FAU - Lazaro, Conxi AU - Lazaro C AD - Hereditary Cancer Programme, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research, L'Hospitalet del Llobregat, 08908 Barcelona, Spain. FAU - Chu, Mandy F AU - Chu MF AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Haight, Jillian AU - Haight J AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Tinto, Paul AU - Tinto P AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Silvester, Jennifer AU - Silvester J AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Cescon, David W AU - Cescon DW AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. FAU - Petit, Anna AU - Petit A AD - Department of Pathology, Bellvitge University Hospital, Oncobell, Bellvitge Institute for Biomedical Research, L'Hospitalet del Llobregat, 08908 Barcelona, Spain. FAU - Pettersson, Sven AU - Pettersson S AD - Department of Molecular Biotechnology and Health Sciences, Tumor and Cell Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden. FAU - Pollard, Jeffrey W AU - Pollard JW AD - Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom. FAU - Mak, Tak W AU - Mak TW AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; tak.mak@uhnresearch.ca Chiara.Gorrini@uhnresearch.ca. FAU - Pujana, Miguel A AU - Pujana MA AD - Breast Cancer and Systems Biology Laboratory, Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research, L'Hospitalet del Llobregat, 08908 Barcelona, Spain. FAU - Cappello, Paola AU - Cappello P AD - Molecular Biotechnology Center, University of Turin, 10126 Turin, Italy. AD - Department of Molecular Biotechnologies and Health Science, University of Turin, 10126 Turin, Italy. FAU - Gorrini, Chiara AU - Gorrini C AD - The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; tak.mak@uhnresearch.ca Chiara.Gorrini@uhnresearch.ca. LA - eng GR - FDN-143268/CIHR/Canada GR - Wellcome Trust/United Kingdom GR - 101067/Z/13/Z/WT_/Wellcome Trust/United Kingdom GR - MOP-86707/CAPMC/CIHR/Canada GR - MR/N022556/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190207 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (BRCA1 Protein) RN - 0 (BRCA1 protein, human) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, Aryl Hydrocarbon) RN - DA87705X9K (Erlotinib Hydrochloride) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adult MH - Amphiregulin/*genetics MH - Animals MH - Apoptosis/drug effects MH - BRCA1 Protein/*genetics MH - Breast Neoplasms/drug therapy/*genetics/pathology MH - ErbB Receptors/genetics MH - Erlotinib Hydrochloride/administration & dosage MH - Female MH - Gene Expression Regulation, Neoplastic MH - Homeostasis/genetics MH - Humans MH - Mice MH - Middle Aged MH - Oxidation-Reduction/drug effects MH - Reactive Oxygen Species/metabolism MH - Receptors, Aryl Hydrocarbon/*genetics MH - Tumor Microenvironment/genetics PMC - PMC6397541 OTO - NOTNLM OT - amphiregulin OT - aryl hydrocarbon receptor OT - reactive oxygen species OT - triple-negative breast cancer OT - tumor-associated macrophages COIS- The authors declare no conflict of interest. EDAT- 2019/02/09 06:00 MHDA- 2019/05/03 06:00 PMCR- 2019/08/07 CRDT- 2019/02/09 06:00 PHST- 2019/02/09 06:00 [pubmed] PHST- 2019/05/03 06:00 [medline] PHST- 2019/02/09 06:00 [entrez] PHST- 2019/08/07 00:00 [pmc-release] AID - 1815126116 [pii] AID - 201815126 [pii] AID - 10.1073/pnas.1815126116 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3604-3613. doi: 10.1073/pnas.1815126116. Epub 2019 Feb 7.