Journal Article

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

Petit, Anna, Cescon, David W., Silvester, Jennifer, Kubli, Shawn P., Cassetta, Luca, Soong, Daniel, Göbl, Christoph, Chu, Mandy F., Ramachandran, Parameswaran, Mak, Tak W., Palomero, Luis, Herranz, Carmen, Pettersson, Sven, Duncan, Gordon, Zhou, Wenjing, Wakeham, Andrew, Berger, Thorsten, Yarden, Yosef, Bassi, Christian, Cappello, Paola, Jones, Lisa, Haight, Jillian, Snow, Bryan, Pujana, Miguel A., Pollard, Jeffrey W., Roux, Cecilia, Lazaro, Conxi, Thu, Kelsie L., Baniasadi, Shakiba P., Lindzen, Moshit, Tinto, Paul, Gorrini, Chiara, Jafari, Soode Moghadas

2019

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Adult / Amphiregulin / Amphiregulin - genetics / Animal models / Animals / Anticancer properties / Antioxidants / Apoptosis - drug effects / Aromatic compounds / Biological Sciences / BRCA1 protein / BRCA1 Protein - genetics / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer / Cell Biology / Chemokines / Combinatorial analysis / Enzyme inhibitors / Epidermal growth factor / Epidermal growth factor receptors / ErbB Receptors - genetics / Erlotinib Hydrochloride - administration & dosage / Female / Gene Expression Regulation, Neoplastic / Growth factors / Homeostasis / Homeostasis - genetics / Humans / Infiltration / Kinases / Macrophages / Metastases / Mice / Middle Aged / Monocytes / Organic chemistry / Oxidation-Reduction - drug effects / PNAS Plus / Protein-tyrosine kinase / Reactive oxygen species / Reactive Oxygen Species - metabolism / Receptors, Aryl Hydrocarbon - genetics / Transcription activation / Tumor Microenvironment - genetics / Tumors / Tyrosine