The Aryl-hydrocarbon Receptor (AhR) as a Therapeutic Target in Human Breast Cancer

Abstract

Breast cancer is currently the most prevalent malignancy among women in industrialized countries, and 1 in 8 women living in the United States will develop the disease at some point in her lifetime. Although the incidence of breast cancer has increased 0.3% per year since 1990, the mortality rate has decreased by 2% per year since 1990 due to improvements in treatment and early detection. New treatment strategies and a better molecular understanding of the disease will be important to continue the progress science has made against this disease. The aryl-hydrocarbon receptor (AhR) has been traditionally associated with activation by environmental contaminants, acute toxicity, and cancer risks associated with exposures. However, the AhR has been highly conserved throughout evolution suggesting an important biological role for the receptor independent of its response to environmental contaminants. There is a significant body of evidence indicating the AhR plays a role in breast epithelial cell differentiation and that receptor agonists can inhibit breast cancer growth. A 50% reduction in estrousinduced terminal end buds was observed in the mammary glands of AhR knockout animals when compared to wild type suggesting a role for the AhR in mammary development. In 2 independent rodent cancer bioassays, treatment with the AhR agonist 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) significantly reduced the incidence of spontaneous rat mammary tumors. These and other studies support the premise that the AhR plays a fundamental role in breast epithelial cell differentiation. This review provides a brief summary of the current evidence that the AhR may be an important pharmacological target for treating human breast cancer.

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

“…The AhR has been reported to have effects on the immune response, cell cycle progression, as well as crosstalk with both BRCA1 and the ER. Studies also demonstrate an association with normal mammary gland development . It has recently been reported that in addition to these factors, the receptor has a prognostic role.…”

Illuminating kinase inhibitors biology by cell signaling profiling

“…5B). These off-target effects can be detrimental in one clinical settings ( 42, 43 ) but beneficial in others ( 44, 45 ). Therefore, the TFAP approach provides clear quantitative metrics for PKI evaluation, including the on-target and off-target signatures and the concentration ranges wherein these activities dominate.…”

Extracellular acidosis stimulates breast cancer cell motility through aryl hydrocarbon receptor and c‐src kinase activation

“…15,29,30 AhR plays an important role in tumor development 23 acting as a tumor suppressor or a tumorigenic factor, depending on the ligand, the AhR signaling pathways activated and the cellular context. For instance, the stimulation of nuclear AhR signaling is related to breast cancer prevention, 29,31 and the AhR ligands omeprazole and tranilast decrease MDA-MB-231 cell motility. 32,33 However, the AhR/c-Src axis activation promotes breast alterations and tumor progression 34,35 and the AhR agonist HCB and chlorpyrifos boost breast cancer cell migration and invasion.…”