Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development.

Christoph F A Vogel,Colleen Sweeney,Juliann Jugan,Yi He,Yasuhiro Ishihara,Andrea Rossi,Alexander D Borowsky,Christian Vogeley,Alejandro Castaneda,Michele A La Merrill,Hidetoshi Mori,Sarah Y Kado,Thomas Haarmann-Stemmann,Gwendal Lazennec,Carla Dahlem

doi:10.3389/fimmu.2021.625346

Abstract

Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to known human carcinogens including dioxins can lead to the promotion of breast cancer. While the repressor protein of the AhR (AhRR) blocks the canonical AhR pathway, the function of AhRR in the development of breast cancer is not well-known. In the current study we examined the impact of suppressing AhR activity using its dedicated repressor protein AhRR. AhRR is a putative tumor suppressor and is silenced in several cancer types, including breast, where its loss correlates with shorter patient survival. Using the AhRR transgenic mouse, we demonstrate that AhRR overexpression opposes AhR-driven and inflammation-induced growth of mammary tumors in two different murine models of breast cancer. These include a syngeneic model using E0771 mammary tumor cells as well as the Polyoma Middle T antigen (PyMT) transgenic model. Further AhRR overexpression or knockout of AhR in human breast cancer cells enhanced apoptosis induced by chemotherapeutics and inhibited the growth of mouse mammary tumor cells. This study provides the first in vivo evidence that AhRR suppresses mammary tumor development and suggests that strategies which lead to its functional restoration and expression may have therapeutic benefit.

Highlights

Environmental exposure to toxicants including dioxins and many other dioxin-like compounds (DLC) which bind to the aryl hydrocarbon receptor (AhR) and activate the AhR signaling pathway, is associated with the development of malignancies including breast cancer [1,2,3,4]
We demonstrated that overexpression of AhR Repressor (AhRR) in vitro, in human breast cancer cells, inhibits cell survival mediated by AhR [17]
In the syngeneic E0771 model, we demonstrate that AhRR overexpression inhibits basal and AhR-driven (TCDD-stimulated) mammary tumor cell growth

Summary

Introduction

Environmental exposure to toxicants including dioxins and many other dioxin-like compounds (DLC) which bind to the aryl hydrocarbon receptor (AhR) and activate the AhR signaling pathway, is associated with the development of malignancies including breast cancer [1,2,3,4]. The activated AhR pathway results in changes of the expression profile of cytokines and immune modulatory enzymes which may contribute to the carcinogenic effects of AhR-activating toxicants [3]. The repressor protein of the AhR (AhRR) has been found to suppress the canonical AhR signaling pathway as well as the activation of inflammatory cytokines [6, 7]. Literature indicates that the AhR regulates normal development of the mammary gland [10,11,12] revealing this tissue as a sensitive target of environmental pollutants containing AhR activating chemicals

Methods

Results

Conclusion