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

Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3604-3613. doi: 10.1073/pnas.1815126116. Epub 2019 Feb 7.


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.

Keywords: amphiregulin; aryl hydrocarbon receptor; reactive oxygen species; triple-negative breast cancer; tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amphiregulin / genetics*
  • Animals
  • Apoptosis / drug effects
  • BRCA1 Protein / genetics*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • ErbB Receptors / genetics
  • Erlotinib Hydrochloride / administration & dosage
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeostasis / genetics
  • Humans
  • Mice
  • Middle Aged
  • Oxidation-Reduction / drug effects
  • Reactive Oxygen Species / metabolism
  • Receptors, Aryl Hydrocarbon / genetics*
  • Tumor Microenvironment / genetics


  • AREG protein, human
  • Amphiregulin
  • BRCA1 Protein
  • BRCA1 protein, human
  • Reactive Oxygen Species
  • Receptors, Aryl Hydrocarbon
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors