Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br AHR expression in cancer Perhaps the earliest indicator

    2024-03-21


    AHR expression in cancer Perhaps the earliest indicator that the AHR might play an ongoing role in tumorigenesis, independent of its role in generating mutations, was the demonstration that non-genotoxic 2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD) is a carcinogen in animals and humans [7]. Although still a matter of some debate, human exposure to this Class 1 carcinogen [8] may be associated with an increased risk of hepatobiliary, prostate, digestive tract and breast cancers and increased frequency of hematologic neoplasia [9–12]. TCDD is highly persistent and is capable of sustaining AHR signaling for long periods of time in vitro and in vivo[13]. Therefore, it might be postulated that conditions under which the AHR is chronically active would predispose cells to malignant transformation or accelerate the transition of relatively benign growths into full blown, metastatic cancers. Evidence in support of this hypothesis has come from many animal models of human cancer [14–23]. More specifically, the AHR is hyper-expressed in a variety of human and rodent tumors including breast [24], lung [25,26], gastric [27], ARCA Cy3 EGFP [17], ovarian [28], pancreatic [29], and oral [30] carcinomas, Hodgkin's lymphoma [31], chronic lymphocytic leukemia [31] and adult T-cell leukemia [32]. Notably, some of our earlier studies indicated rat breast cancers express as much as 30 fold more Ahr mRNA than normal breast tissue [33]. While estimates of AHR expression across 1036 different human tumor cell lines characterized in the Cancer Cell Line Encyclopedia (CCLE) [34] are more modest (Figure 1), they still suggest a general trend towards high level AHR expression relative to normal tissue, especially in solid tumors. It should be noted that these assays do not always distinguish between AHR expressed in malignant cells and AHR expressed in the surrounding microenvironment. Indeed, our earliest studies revealed high level AHR expression both in malignant cells and surrounding fibroblast-like cells within the tumor [33].
    AHR hyper-activity, endogenous ligands, and an AHR-TDO/IDO-driven amplification loop in cancer In addition to being hyper-expressed, the AHR also appears to be “constitutively active” in a diverse array of human cancers including glioblastomas, adult T cell leukemias and breast, oral, lung, liver, and prostate adenocarcinomas [17,20,30,32,35–46]. At least in breast cancers, constitutive AHR activity can be tracked by levels of CYP1B1 mRNA [24]. Indeed, CYP1B1 seems to be a good marker for constitutive AHR activity in cancer since, among all cancer cell lines characterized in the CCLE, CYP1B1 is the nearest gene (transcript) neighbor to the AHR[35]. This fact may be particularly relevant for breast cancers inasmuch as CYP1B1 catalyzes the production of mutagenic and estrogenic 4-hydroxy-estradiol from estradiol. Since no functionally significant mutations in the AHR have been described in any form of cancer, this chronic AHR activity likely reflects the presence of endogenous ligands [35,42]. An early indication of the presence of endogenous AHR ligands in malignant cells came from studies demonstrating that CYP1A1 inhibition increases and ectopic CYP1A1 expression decreases baseline AHR activity, a result attributed to the ability of CYP1A1 to metabolize an undefined endogenous ligand(s) [38,47,48]. The nature of these endogenous ligands has been the subject of many studies within the fields of toxicology and, more recently, oncology. A number of candidate endogenous AHR ligands have been proposed including heme-derived molecules, arachidonic acid metabolites, and tryptophan metabolites (reviewed in Ref. [49]). Of those, tryptophan metabolites, particularly those generated in the kynurenine pathway of tryptophan catabolism, seem to be the most relevant in the cancer setting. For example, l-kynurenine, an endogenous AHR ligand and proximal product of the dominant kynurenine pathway of tryptophan metabolism, is produced by human glioblastomas and drives tumor invasion through an AHR-dependent mechanism [42]. Furthermore, kynurenine, and a more distal metabolite and more potent AHR ligand, xanthurenic acid, are present in ER−/PR−/Her2− breast cancer cell lines [35,50] at high enough intracellular concentrations (∼90 μM and ∼10 μM respectively) to drive chronic AHR activity [35]. The production of these tryptophan-derived endogenous AHR ligands by malignant cells takes on added significance in the light of many studies demonstrating aberrant tryptophan metabolism in multiple cancer types and implicating these metabolites as markers for and/or contributors to these cancers [51,52].