Figure 2.

AhR in breast cancer and the role of dietary compounds. High levels of AhR induce malignant transformation in HMEC cells characterized by EMT, increased growth rates, abrogated cell cycle control, and increased migration and invasive potential. Exposure to exogenous AhR agonists such as halogenated aromatic hydrocarbons (HAH), polycyclic aromatic hydrocarbons (PAH), and other dioxin-like compounds (DLC) leads to activation of AhR in the mammary gland. The endogenous AhR agonist kynurenine is produced through metabolism of tryptophan by tryptophan-2,3-dioxygenase (TDO)2, which can be upregulated in the tumor stroma and intratumorally in TNBC; or Indoleamine 2,3-dioxygenase (IDO), which is induced in stromal cells by cancer cell upregulation of COX-II. Activated AhR induces expression of many key genes in BC including 1) COX-2, which enhances invasive capacity and metastatic potential of mammary tumors and may cause sustained hyperactivation of AhR through positive feedback by upregulating IDO in stromal cells leading to kynurenine accumulation; 2) CYP1B1, which metabolizes estradiol (E2) to the mutagenic 4OH-Estradiol metabolite; and 3) SLUG, a transcription factor largely involved in EMT. The activated AhR also mediates epigenetic silencing of BRCA1, which would otherwise function to maintain genomic stability through the stable homologous recombination pathway. Closed arrowheads represent stimulus. Blunted lines represent inhibition.