High AHR expression in breast tumors correlates with expression of genes from several signaling pathways namely inflammation and endogenous tryptophan metabolism

Increasing epidemiological and animal experimental data provide substantial support for the role of aryl hydrocarbon receptor (AhR) in mammary tumorigenesis. The effects of AhR have been clearly demonstrated in rodent models of breast carcinogenesis and in several established human breast cancer cell lines following exposure to AhR ligands or AhR overexpression. However, relatively little is known about the role of AhR in human breast cancers. AhR has always been considered to be a regulator of toxic and carcinogenic responses to environmental contaminants such as TCDD (dioxin) and benzo[a]pyrene (BaP). The aim of this study was to identify the type of breast tumors (ERα-positive or ERα-negative) that express AHR and how AhR affects human tumorigenesis. The levels of AHR, AHR nuclear translocator (ARNT) and AHR repressor (AHRR) mRNA expression were analyzed in a cohort of 439 breast tumors, demonstrating a weak association between high AHR expression and age greater than fifty years and ERα-negative status, and HR-/ERBB2 breast cancer subtypes. AHRR mRNA expression was associated with metastasis-free survival, while AHR mRNA expression was not. Immunohistochemistry revealed the presence of AhR protein in both tumor cells (nucleus and/or cytoplasm) and the tumor microenvironment (including endothelial cells and lymphocytes). High AHR expression was correlated with high expression of several genes involved in signaling pathways related to inflammation (IL1B, IL6, TNF, IL8 and CXCR4), metabolism (IDO1 and TDO2 from the kynurenine pathway), invasion (MMP1, MMP2 and PLAU), and IGF signaling (IGF2R, IGF1R and TGFB1). Two well-known ligands for AHR (TCDD and BaP) induced mRNA expression of IL1B and IL6 in an ERα-negative breast tumor cell line. The breast cancer ER status likely influences AhR activity involved in these signaling pathways. The mechanisms involved in AhR activation and target gene expression in breast cancers are also discussed.

[1]  D. Romagnolo,et al.  Constitutive expression of AhR and BRCA-1 promoter CpG hypermethylation as biomarkers of ERα-negative breast tumorigenesis , 2015, BMC Cancer.

[2]  A. D’Alessandro,et al.  A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. , 2015, Cancer research.

[3]  M. Pocard,et al.  Dietary exposure in utero and during lactation to a mixture of genistein and an anti-androgen fungicide in a rat mammary carcinogenesis model. , 2015, Reproductive toxicology.

[4]  G. Prendergast,et al.  Accumulation of an Endogenous Tryptophan-Derived Metabolite in Colorectal and Breast Cancers , 2015, PloS one.

[5]  Kyung-Chul Choi,et al.  Cytochrome P450 1 family and cancers , 2015, The Journal of Steroid Biochemistry and Molecular Biology.

[6]  G. Perdew,et al.  Aryl hydrocarbon receptor ligands in cancer: friend and foe , 2014, Nature Reviews Cancer.

[7]  Jun Fan,et al.  Endogenous aryl hydrocarbon receptor promotes basal and inducible expression of tumor necrosis factor target genes in MCF-7 cancer cells. , 2014, Biochemical pharmacology.

[8]  S. Safe,et al.  The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis , 2014, BMC Cancer.

[9]  B. Stockinger,et al.  The aryl hydrocarbon receptor: multitasking in the immune system. , 2014, Annual review of immunology.

[10]  H. Gogas,et al.  Differential Expression of the Insulin-Like Growth Factor Receptor among Early Breast Cancer Subtypes , 2014, PloS one.

[11]  Takashi Suzuki,et al.  Aryl Hydrocarbon Receptor in Breast Cancer—A Newly Defined Prognostic Marker , 2014, Hormones and Cancer.

[12]  A. von Deimling,et al.  Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR , 2014, Oncotarget.

[13]  Yibin Kang,et al.  Knockdown of aberrantly upregulated aryl hydrocarbon receptor reduces tumor growth and metastasis of MDA‐MB‐231 human breast cancer cell line , 2013, International journal of cancer.

[14]  Xinming Wang,et al.  Role of aryl hydrocarbon receptor in cancer. , 2013, Biochimica et biophysica acta.

[15]  F. Quintana,et al.  Aryl Hydrocarbon Receptor Control of Adaptive Immunity , 2013, Pharmacological Reviews.

[16]  Jianmei Wu,et al.  Reactivation of Estrogen Receptor α by Vorinostat Sensitizes Mesenchymal-Like Triple-Negative Breast Cancer to Aminoflavone, a Ligand of the Aryl Hydrocarbon Receptor , 2013, PloS one.

[17]  S. Safe,et al.  Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. , 2013, Toxicological sciences : an official journal of the Society of Toxicology.

[18]  S. Eltom,et al.  The Aryl Hydrocarbon Receptor: A Target for Breast Cancer Therapy , 2013, Journal of cancer therapy.

[19]  X. Coumoul,et al.  The AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications. , 2013, Drug discovery today.

[20]  W. Wick,et al.  Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. , 2012, Cancer research.

[21]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[22]  S. Fenton,et al.  Perinatal environmental exposures affect mammary development, function, and cancer risk in adulthood. , 2012, Annual review of pharmacology and toxicology.

[23]  Bin Zhao,et al.  Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[24]  M. Weller,et al.  An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor , 2011, Nature.

[25]  P. Brambilla,et al.  Dioxin Exposure and Cancer Risk in the Seveso Women’s Health Study , 2011, Environmental health perspectives.

[26]  Dalei Wu,et al.  Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression. , 2011, Archives of biochemistry and biophysics.

[27]  S. Eltom,et al.  Malignant transformation of mammary epithelial cells by ectopic overexpression of the aryl hydrocarbon receptor. , 2011, Current cancer drug targets.

[28]  Lyle D Burgoon,et al.  Genome-wide computational analysis of dioxin response element location and distribution in the human, mouse, and rat genomes. , 2011, Chemical research in toxicology.

[29]  J. Fechner,et al.  An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells , 2010, The Journal of Immunology.

[30]  S. Amin,et al.  Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties. , 2010, Chemical research in toxicology.

[31]  Russell S. Thomas,et al.  Activation of the aryl-hydrocarbon receptor inhibits invasive and metastatic features of human breast cancer cells and promotes breast cancer cell differentiation. , 2010, Molecular endocrinology.

[32]  Paolo Grillo,et al.  Cancer incidence in the population exposed to dioxin after the "Seveso accident": twenty years of follow-up , 2009, Environmental health : a global access science source.

[33]  S. Safe,et al.  The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. , 2009, Endocrine-related cancer.

[34]  P. Fernández-Salguero,et al.  Dioxin Receptor Deficiency Impairs Angiogenesis by a Mechanism Involving VEGF-A Depletion in the Endothelium and Transforming Growth Factor-β Overexpression in the Stroma* , 2009, The Journal of Biological Chemistry.

[35]  F. Matsumura,et al.  Characterization of MCF mammary epithelial cells overexpressing the Arylhydrocarbon receptor (AhR) , 2009, BMC Cancer.

[36]  M. E. Hahn,et al.  Regulation of constitutive and inducible AHR signaling: complex interactions involving the AHR repressor. , 2009, Biochemical pharmacology.

[37]  G. Perdew,et al.  Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells. , 2008, Cancer research.

[38]  Fred Hirsch,et al.  The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. , 2008, The Journal of clinical investigation.

[39]  Fumio Matsumura,et al.  Involvement of RelB in aryl hydrocarbon receptor-mediated induction of chemokines. , 2007, Biochemical and biophysical research communications.

[40]  X. Coumoul,et al.  The aryl hydrocarbon receptor, more than a xenobiotic‐interacting protein , 2007, FEBS letters.

[41]  D. Schrenk,et al.  Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models. , 2006, Molecular nutrition & food research.

[42]  D. Seldin,et al.  A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis , 2006, Biological chemistry.

[43]  M. Q. Kemp,et al.  The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen. , 2006, Cancer research.

[44]  B. Jeffy,et al.  An estrogen receptor-alpha/p300 complex activates the BRCA-1 promoter at an AP-1 site that binds Jun/Fos transcription factors: repressive effects of p53 on BRCA-1 transcription. , 2005, Neoplasia.

[45]  P. A. Pérez-Mancera,et al.  Immortalized Mouse Mammary Fibroblasts Lacking Dioxin Receptor Have Impaired Tumorigenicity in a Subcutaneous Mouse Xenograft Model* , 2005, Journal of Biological Chemistry.

[46]  V. Kosma,et al.  Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Breast Cancer with a Special Reference to Activator Protein-2, HER2, and Prognosis , 2004, Clinical Cancer Research.

[47]  M. Denison,et al.  Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. , 2003, Annual review of pharmacology and toxicology.

[48]  C. Tohyama,et al.  Modulation of oestrogen receptor signalling by association with the activated dioxin receptor , 2003, Nature.

[49]  Ruthann A Rudel,et al.  Environmental pollutants and breast cancer , 2007, Cancer.

[50]  Linda S Birnbaum,et al.  Cancer and developmental exposure to endocrine disruptors. , 2002, Environmental health perspectives.

[51]  S. Safe,et al.  Crosstalk between estrogen receptor α and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes , 2000, FEBS letters.

[52]  J. Kaprio,et al.  Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. , 2000, The New England journal of medicine.

[53]  S. Safe,et al.  Development of selective aryl hydrocarbon receptor modulators for treatment of breast cancer. , 1999, Expert opinion on investigational drugs.

[54]  M. Gallo,et al.  Ah Receptor and NF-κB Interactions, a Potential Mechanism for Dioxin Toxicity* , 1999, The Journal of Biological Chemistry.

[55]  Jun Wang,et al.  Prenatal TCDD and predisposition to mammary cancer in the rat. , 1998, Carcinogenesis.

[56]  C. Jefcoate,et al.  Characterization of CYP1B1 and CYP1A1 expression in human mammary epithelial cells: role of the aryl hydrocarbon receptor in polycyclic aromatic hydrocarbon metabolism. , 1998, Cancer research.

[57]  S Guercilena,et al.  Dioxin Exposure and Cancer Risk: A 15‐Year Mortality Study after the “Seveso Accident” , 1997, Epidemiology.

[58]  J Benichou,et al.  Proportion of breast cancer cases in the United States explained by well-established risk factors. , 1995, Journal of the National Cancer Institute.

[59]  C. Vogel,et al.  Different response of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive genes in human breast cancer MCF-7 and MDA-MB 231 cells. , 1995, Archives of biochemistry and biophysics.

[60]  T. Pineau,et al.  Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor , 1995, Science.

[61]  E. Milgrom,et al.  Immunocytochemical study with monoclonal antibodies to progesterone receptor in human breast tumors. , 1987, Cancer research.

[62]  J. Hanley,et al.  The meaning and use of the area under a receiver operating characteristic (ROC) curve. , 1982, Radiology.

[63]  C. Wade,et al.  Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. , 1978, Toxicology and applied pharmacology.

[64]  Olivier Humblet,et al.  Environmental pollutants and breast cancer: epidemiologic studies. , 2007, Cancer.

[65]  Y. Fujii‐Kuriyama,et al.  Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. , 1999, Genes & development.

[66]  M. Gallo,et al.  Ah receptor and NF-kappaB interactions, a potential mechanism for dioxin toxicity. , 1999, The Journal of biological chemistry.

[67]  M. Wright.  Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. , 1996, Human & experimental toxicology.

[68]  D. Cox.  Regression Models and Life-Tables , 1972 .

[69]  D.,et al.  Regression Models and Life-Tables , 2022 .