Ron, and X-associated protein 2. Upon binding to aromatic ligands, toxins, drugs, phytochemicals, and sterols, the AhR-ligand complex shuttles from cytoplasm to the nucleus, where it heteromerises with the AhR nuclear translocator (Arnt) to form the transcription complex able to bind to xenobiotic responsive elements (XRE) DNA-binding motifs located in the promoter region of the target drug metabolising genes, such as phase I (mainly, Cyp1 subfamily) and II metabolising enzymes and Nrf2 [156?58]. One of the downstream targets for AhR is BCRP encoded by ABCC3 gene [159?61]. The coordinate AhR- and Nrf2-dependent transcriptional regulation of human UGTs by utilising both XRE- and ARE-binding motifs takes place to protect cells from xenobiotic and oxidative stresses [162]. The elegant study with genetically modified mice has clearly demonstrated that Nrf2 is required for ligand-associated induction of classical “AhR battery” genes NQO1, GST isoforms, and UGTs [163]. Apart from metabolic enzymes, a number of growth factors, cytokines, chemokines, and their receptors are downstream gene targets for activated AhR [164, 165]. AhR is also functionally connected with epidermal growth factor receptor, presumably, through NF-Bregulated pathway [166], thus influencing the epithelial cell proliferation. AhR can also cross-talk and directly interact with proteins involved in major redox-regulated signalling pathways such as NF-B and various kinases such as Src, JNK, p38, and MAPK [167] and with oestrogen receptors to mediate oestrogen metabolism [168, 169]. Recent studies have unraveled unsuspected physiological roles and novel alternative ligand-specific pathways for this receptor that allowed hypothesising numerous pharmacological roles of10 AhR ligands useful for the development of a new generation of anti-inflammatory and anticancer drugs [159, 170]. The AhR-mediated regulation of aromatic hydrocarbons metabolism has been implicated in a variety of cancers [164, 171] affecting different stages of carcinogenesis. If metabolic activation of the organic molecules increased the levels of their adducts with DNA thus promoting cancer initiation, anticancer drug- or toxin-induced AhR activation played a pivotal role in cancer promotion and progression [172, 173]. Elevated AhR expression associated with constitutive nonligand activation has been found in several cancers as evidenced by the nuclear localisation of AhR and induced downstream gene Cyp1A1 [174, 175]. Stable knockdown of AhR decreased the tumorigenic and metastatic properties of AG-490 web breast cancer cell line in vitro and in vivo. On the other hand, AhR overexpression in nontumour human mammary epithelial cells NVP-AUY922 clinical trials transformed them in cells with malignant phenotype [176]. Of importance, AhR knockdown downregulated the expression of ABCC3; overexpression of this gene in breast cancer has been strongly associated with acquired MDR [177] and resistance to paclitaxel, a drug widely used in the treatment of metastatic breast cancer [178]. Inherited polymorphisms in AhR, for example, substitution Arg554Lys, and its machinery [179, 180] or presence of endogenous ligandsstimulators for the receptor (cAMP, bilirubin, prostaglandins, oxidative lipids, etc.) could be implicated into inherited MDR. To suppress AhR transcription pharmacologically several approaches have been proposed, including the modulation of protein-protein interaction between transcription factor, coactivators, and corepressors [160, 167, 181].Ron, and X-associated protein 2. Upon binding to aromatic ligands, toxins, drugs, phytochemicals, and sterols, the AhR-ligand complex shuttles from cytoplasm to the nucleus, where it heteromerises with the AhR nuclear translocator (Arnt) to form the transcription complex able to bind to xenobiotic responsive elements (XRE) DNA-binding motifs located in the promoter region of the target drug metabolising genes, such as phase I (mainly, Cyp1 subfamily) and II metabolising enzymes and Nrf2 [156?58]. One of the downstream targets for AhR is BCRP encoded by ABCC3 gene [159?61]. The coordinate AhR- and Nrf2-dependent transcriptional regulation of human UGTs by utilising both XRE- and ARE-binding motifs takes place to protect cells from xenobiotic and oxidative stresses [162]. The elegant study with genetically modified mice has clearly demonstrated that Nrf2 is required for ligand-associated induction of classical “AhR battery” genes NQO1, GST isoforms, and UGTs [163]. Apart from metabolic enzymes, a number of growth factors, cytokines, chemokines, and their receptors are downstream gene targets for activated AhR [164, 165]. AhR is also functionally connected with epidermal growth factor receptor, presumably, through NF-Bregulated pathway [166], thus influencing the epithelial cell proliferation. AhR can also cross-talk and directly interact with proteins involved in major redox-regulated signalling pathways such as NF-B and various kinases such as Src, JNK, p38, and MAPK [167] and with oestrogen receptors to mediate oestrogen metabolism [168, 169]. Recent studies have unraveled unsuspected physiological roles and novel alternative ligand-specific pathways for this receptor that allowed hypothesising numerous pharmacological roles of10 AhR ligands useful for the development of a new generation of anti-inflammatory and anticancer drugs [159, 170]. The AhR-mediated regulation of aromatic hydrocarbons metabolism has been implicated in a variety of cancers [164, 171] affecting different stages of carcinogenesis. If metabolic activation of the organic molecules increased the levels of their adducts with DNA thus promoting cancer initiation, anticancer drug- or toxin-induced AhR activation played a pivotal role in cancer promotion and progression [172, 173]. Elevated AhR expression associated with constitutive nonligand activation has been found in several cancers as evidenced by the nuclear localisation of AhR and induced downstream gene Cyp1A1 [174, 175]. Stable knockdown of AhR decreased the tumorigenic and metastatic properties of breast cancer cell line in vitro and in vivo. On the other hand, AhR overexpression in nontumour human mammary epithelial cells transformed them in cells with malignant phenotype [176]. Of importance, AhR knockdown downregulated the expression of ABCC3; overexpression of this gene in breast cancer has been strongly associated with acquired MDR [177] and resistance to paclitaxel, a drug widely used in the treatment of metastatic breast cancer [178]. Inherited polymorphisms in AhR, for example, substitution Arg554Lys, and its machinery [179, 180] or presence of endogenous ligandsstimulators for the receptor (cAMP, bilirubin, prostaglandins, oxidative lipids, etc.) could be implicated into inherited MDR. To suppress AhR transcription pharmacologically several approaches have been proposed, including the modulation of protein-protein interaction between transcription factor, coactivators, and corepressors [160, 167, 181].
