The aryl hydrocarbon receptor (AhR) mediates resistance to apoptosis induced in breast cancer cells

Abstract

The aryl hydrocarbon receptor (AhR) is well known as a ligand binding transcription factor regulating various biological effects. Previously we have shown that long-term exposure to estrogen in breast cancer cells caused not only down regulation of estrogen receptor (ER) but also overexpression of AhR. The AhR interacts with several cell signaling pathways associated with induction of tyrosine kinases, cytokines and growth factors which may support the survival roles of AhR escaping from apoptosis elicited by a variety of apoptosis inducing agents in breast cancer. In this study, we studied the anti-apoptotic role of AhR in different breast cancer cells when apoptosis was induced by exposure to UV light and chemotherapeutic agents. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in AhR overexpressing breast cancer cells effectively suppressed the apoptotic response induced by UV-irradiation, doxorubicin, lapatinib and paclitaxel. The anti-apoptotic response of TCDD was uniformly antagonized by the treatment with 3′methoxy-4′nitroflavone (MNF), a specific antagonist of AhR. TCDD’s survival action of apoptosis was accompanied with the induction of well-known inflammatory genes, such as cyclooxygenase-2 (COX-2) and NF-κB subunit RelB. Moreover, TCDD increased the activity of the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO), which metabolizes tryptophan to kynurenine (Kyn) and mediates tumor immunity. Kyn also acts as an AhR ligand like TCDD, and kyn induced an anti-apoptotic response in breast cancer cells. Accordingly, our present study suggests that AhR plays a pivotal role in the development of breast cancer via the suppression of apoptosis, and provides an idea that the use of AhR antagonists with chemotherapeutic agents may effectively synergize the elimination of breast cancer cells.

The aryl hydrocarbon receptor repressor – More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer

“…Interestingly, a recent meta-analysis found that exposure and increased blood levels of TCDD are significantly associated with the mortality caused by non-Hodgkin’s lymphoma (123). Furthermore, our previous reports strongly support the function of AhR to mediate an anti-apoptotic response in human lymphoma cells (124) and the vital role of RelB in AhR-mediated apoptotic resistance in human breast cancer cells (61, 66). Because both, AhRR and RelB, may form heterodimers with ARNT (figure 2), it is essential to understand the possible interaction of AhRR/ARNT with RelB and its consequences in regulation of cellular processes, like cell-cycling and apoptosis.…”

“…AhR is overexpressed and/or over-activated in various solid cancers (41–43), in which it may drive proliferation, apoptosis resistance, extracellular matrix degradation, and immunosuppression (60–66). Thus, AhR’s opponent may exhibit tumor-suppressive properties as depicted in figure 2.…”

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

“…In addition, recent studies from our laboratory and others have demonstrated the pivotal role of AhR/CYP1A1 in development of breast cancer. In that, it has been previously reported that TCDD, AhR ligand and potent CYP1A1 inducer, increased human breast cancer MCF-7 cell proliferation and the number and size of the mammospheres (CSC populations) [21] via the suppression of apoptosis [22]. In addition, Maayah et al, have demonstrated that inhibition of AhR/CYP1A1 pathway protects against breast cancer initiation and adduct formation in human epithelial breast MCF10A cells [23].…”

Nano-enabled delivery of diverse payloads across complex biological barriers

“…For example, in work with rat intestinal epithelial cells the overexpression of cyclooxygenase 2, which is elevated in >80% of human colorectal adenocarcinomas, results in increased cellular adhesion and inhibition of apoptosis [34]. Similarly, increased expression of aryl hydrocarbon receptor can induce tumors and may contribute to apoptosis resistance to chemotherapeutic agents in breast cancer cells [35, 36]. Another growth factor, HER2, is overexpressed by 25 to 30 percent in some types of breast cancer cells [37].…”