Activation of the Aryl-Hydrocarbon Receptor Inhibits Invasive and Metastatic Features of Human Breast Cancer Cells and Promotes Breast Cancer Cell Differentiation

Abstract

The current statistics associated with breast cancer continue to show a relatively high recurrence rate together with a poor survival for aggressive metastatic disease. These findings reflect, in part, the pharmaceutical intractability of processes involved in the metastatic process and highlight the need to identify additional drug targets for the treatment of late-stage disease. In the current study, we report that ligand activation of the aryl-hydrocarbon receptor (AhR) inhibits multiple aspects of the metastatic process in a panel of breast cancer cell lines that represent the major breast cancer subtypes. Specifically, it was observed that treatment with exogenous AhR agonists significantly inhibited cell invasiveness and motility in the Boyden chamber assay and inhibited colony formation in soft agar regardless of estrogen receptor (ER), progesterone receptor, or human epidermal growth factor receptor 2 status. Knockdown of the AhR using small interfering RNA duplexes demonstrated that the inhibition of invasiveness was receptor dependent and that endogenous receptor activity was protective in each cell type examined. The inhibition of invasiveness and anchorage-independent growth correlated with the ability of exogenous AhR agonists to promote differentiation. Finally, exogenous AhR agonists were able to promote differentiation in a putative mammary cancer stem cell line. Cumulatively, these results suggest that the AhR plays an important role in mammary epithelial differentiation and, as such, represent a promising therapeutic target for a range of phenotypically distinct human breast cancers.

Activation of Aryl Hydrocarbon Receptor Suppresses Invasion of Esophageal Squamous Cell Carcinoma Cell Lines

“…These data suggest that the BNF-AhR signaling pathway is actively involved in BNF-suppressed ESCC cell invasion. This was also supported by accumulating evidence that activation of the AhR by its ligands could suppress the metastatic process in a variety of cancers [21][22][23] . In contrast, other reports showed that AhR activated enhanced human gastric cancer cell invasion 24 and urothelial cancer invasion 25 .…”

The aryl hydrocarbon receptor ligand ITE inhibits cell proliferation and migration and enhances sensitivity to drug‐resistance in hepatocellular carcinoma

“…It was reported that the activation of AHR with TCDD or DIM could inhibit malignancies in prostate cancer cells as knockdown of AHR would abolish the capability of TCDD or DIM in regulating proliferation, apoptosis, and invasion of PC cells (Yu et al, 2018). In addition, without the activation by xenobiotic ligand, AHR alone was also identified as a suppressor in liver cancer and AHR silence would potentiate invasiveness of breast cancer (Fan et al, 2010; Hall et al, 2010). It should be noted that, however, the antitumor effect of AHR was cell type and/or cancer type‐specific as AHR knockdown showed no effect on OVCAR‐3 cell proliferation nor SKOV‐3 cell migration (Li et al, 2014).…”

The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis

“…One group observed that in the presence of dioxin, the AHR inhibits proliferation in mammary tumor cells and suppresses the ability of these cells to invade normal tissue (235). In a more recent report, it was observed that activation of AHR by various environmental and natural ligands inhibits invasive and metastatic features of human breast cancer cells and promotes their differentiation (236). Activation of the AHR by TCDD inhibits mammary tumor metastasis in a syngeneic mouse model of breast cancer (237).…”