The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study

The aryl hydrocarbon receptor (AhR) is a master regulator of multiple pathways involved in breast cancer, and influences the estrogen receptor alpha (ER) and aromatase/CYP19A1. The purpose of this study was to elucidate the interplay between intratumoral levels of AhR and aromatase, patient characteristics (including AhR and CYP19A1 genotypes), clinicopathological features, and prognosis in breast cancer patients receiving adjuvant treatments. A prospective cohort of 1116 patients with primary breast cancer in Sweden, included 2002–2012, was followed until June 30th 2019 (median 8.7 years). Tumor‐specific AhR (n=920) and aromatase levels (n=816) were evaluated on tissue microarrays using immunohistochemistry. Associations between cytoplasmatic (AhRcyt) and nuclear (AhRnuc) AhR levels, intratumoral aromatase, clinicopathological features, and prognosis in different treatment groups were analyzed. Low AhRcyt levels (n=183) and positive intratumoral aromatase (n=69) were associated with estrogen receptor (ER)– status and more aggressive tumors. Genotypes were not associated with their respective protein levels. The functional AhR Arg554Lys GG genotype was associated with recurrence-free survival in switch-therapy (sequential tamoxifen/aromatase inhibitors (AI) or AI/tamoxifen) treated patients (HRadj 0.42; 95% CI 0.22–0.83). High AhRcyt levels were associated with longer recurrence-free survival during the first 10 years of follow-up among tamoxifen-only treated patients (HRadj 0.40; 95% CI 0.23–0.71) compared to low AhRcyt levels, whereas an almost inverse association was seen in patients with switch-therapy (P interaction=0.023). Intratumoral aromatase had little prognostic impact. These findings warrant confirmation in an independent cohort, preferably in a randomized clinical trial comparing different endocrine regimens. They might also guide the selection of breast cancer patients for clinical trials with selective AhR modulators.

[1]  A. Jayaraman,et al.  Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs) , 2020, International journal of molecular sciences.

[2]  T. Guarnieri.  Aryl Hydrocarbon Receptor Connects Inflammation to Breast Cancer , 2020, International journal of molecular sciences.

[3]  K. Jirström,et al.  Re-evaluation of HER2 status in 606 breast cancers—gene protein assay on tissue microarrays versus routine pathological assessment , 2020, Virchows Archiv.

[4]  K. Isaksson,et al.  Prognostic Impact of Menopausal Hormone Therapy in Breast Cancer Differs According to Tumor Characteristics and Treatment , 2020, Frontiers in Oncology.

[5]  Z. Dai,et al.  Global burden of breast cancer and attributable risk factors in 195 countries and territories, from 1990 to 2017: results from the Global Burden of Disease Study 2017 , 2019, Journal of Hematology & Oncology.

[6]  A. McCluskey,et al.  The aryl hydrocarbon receptor (AhR) as a breast cancer drug target , 2019, Medicinal research reviews.

[7]  E. Winer,et al.  Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  B. Rosner,et al.  Parity, breastfeeding, and breast cancer risk by hormone receptor status and molecular phenotype: results from the Nurses’ Health Studies , 2019, Breast Cancer Research.

[9]  Zhihua Liu,et al.  The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy , 2019, Nature Communications.

[10]  J. Colinge,et al.  The Prognostic Impact of the Aryl Hydrocarbon Receptor (AhR) in Primary Breast Cancer Depends on the Lymph Node Status , 2019, International journal of molecular sciences.

[11]  F. Quintana,et al.  The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease , 2019, Nature Reviews Immunology.

[12]  N. Gooderham,et al.  Ethanol potentiates the genotoxicity of the food-derived mammary carcinogen PhIP in human estrogen receptor-positive mammary cells: mechanistic support for lifestyle factors (cooked red meat and ethanol) associated with mammary cancer , 2018, Archives of Toxicology.

[13]  F. Lallemand,et al.  High AHR expression in breast tumors correlates with expression of genes from several signaling pathways namely inflammation and endogenous tryptophan metabolism , 2018, PloS one.

[14]  S. Safe,et al.  Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target , 2017, Archives of Toxicology.

[15]  G. Gervasini,et al.  Polymorphisms in ABCB1 and CYP19A1 genes affect anastrozole plasma concentrations and clinical outcomes in postmenopausal breast cancer patients , 2017, British journal of clinical pharmacology.

[16]  S. Safe,et al.  The Aryl Hydrocarbon Receptor (AhR) as a Drug Target for Cancer Chemotherapy. , 2017, Current opinion in toxicology.

[17]  Takashi Suzuki,et al.  Aryl hydrocarbon receptor induced intratumoral aromatase in breast cancer , 2017, Breast Cancer Research and Treatment.

[18]  P. Zawierucha,et al.  Induction of expression of aryl hydrocarbon receptor-dependent genes in human HepaRG cell line modified by shRNA and treated with β-naphthoflavone , 2016, Molecular and Cellular Biochemistry.

[19]  C. Ingvar,et al.  Abstract LB-194: AhR Arg554Lys impacts tumor ER expression and endocrine treatment response in breast cancer , 2016 .

[20]  C. Ingvar,et al.  Impacts of smoking on endocrine treatment response in a prospective breast cancer cohort , 2016, British Journal of Cancer.

[21]  C. Ingvar,et al.  CYP1A2 – a novel genetic marker for early aromatase inhibitor response in the treatment of breast cancer patients , 2016, BMC Cancer.

[22]  S. Chittur,et al.  Cross-Talk in the Female Rat Mammary Gland: Influence of Aryl Hydrocarbon Receptor on Estrogen Receptor Signaling , 2015, Environmental health perspectives.

[23]  P. Neven,et al.  CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1–98 trial , 2015, Breast Cancer Research and Treatment.

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

[25]  X. Tong,et al.  Expression of aryl hydrocarbon receptor in relation to p53 status and clinicopathological parameters in breast cancer. , 2014, International Journal of Clinical and Experimental Pathology.

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

[27]  William H. Bisson,et al.  The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells , 2014, Cell Death and Disease.

[28]  Jian-hua Zhou,et al.  A Polymorphism at the 3′-UTR Region of the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor, Anastrozole, in Metastatic Breast Carcinoma , 2013, International journal of molecular sciences.

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

[30]  C. Ingvar,et al.  Given breast cancer, does breast size matter? Data from a prospective breast cancer cohort , 2012, Cancer Causes & Control.

[31]  W. Sauerbrei,et al.  Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and Elaboration , 2012, PLoS medicine.

[32]  L. Hooper.  You AhR What You Eat: Linking Diet and Immunity , 2011, Cell.

[33]  J. Schneider,et al.  RNA expressions of AHR, ARNT and CYP1B1 are influenced by AHR Arg554Lys polymorphism. , 2011, Molecular genetics and metabolism.

[34]  B. Nam,et al.  Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer , 2011, Cancer Chemotherapy and Pharmacology.

[35]  L. Leung,et al.  2,3,7,8-Tetrachlorodibenzo-para-dioxin increases aromatase (CYP19) mRNA stability in MCF-7 cells , 2010, Molecular and Cellular Endocrinology.

[36]  T. Aas,et al.  Breast cancer aromatase expression evaluated by the novel antibody 677: Correlations to intra-tumor estrogen levels and hormone receptor status , 2010, The Journal of Steroid Biochemistry and Molecular Biology.

[37]  G. Hommel,et al.  Judging a plethora of p-values: how to contend with the problem of multiple testing--part 10 of a series on evaluation of scientific publications. , 2010, Deutsches Arzteblatt international.

[38]  B. Rasmussen,et al.  Bmc Cancer , 2022 .

[39]  B. Lloveras,et al.  A Single-Nucleotide Polymorphism in the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor Letrozole in Advanced Breast Carcinoma , 2008, Clinical Cancer Research.

[40]  H. Segner,et al.  Expression of zebra fish aromatase cyp19a and cyp19b genes in response to the ligands of estrogen receptor and aryl hydrocarbon receptor. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[41]  D. Edwards,et al.  The validation of new aromatase monoclonal antibodies for immunohistochemistry—A correlation with biochemical activities in 46 cases of breast cancer , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[42]  D. Edwards,et al.  Validation of new aromatase monoclonal antibodies for immunohistochemistry: progress report , 2003, The Journal of Steroid Biochemistry and Molecular Biology.

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

[44]  S. Safe,et al.  Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action. , 2003, Chemical research in toxicology.

[45]  Stephen Safe,et al.  The Aryl Hydrocarbon Receptor Mediates Degradation of Estrogen Receptor α through Activation of Proteasomes , 2003, Molecular and Cellular Biology.

[46]  A. Astrup,et al.  Obesity : Preventing and managing the global epidemic , 2000 .

[47]  C. Klinge,et al.  The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements , 1999, Molecular and Cellular Endocrinology.

[48]  William D. Dupont,et al.  Power and sample size calculations. A review and computer program. , 1990, Controlled clinical trials.

[49]  Carolyn D. DuSell,et al.  Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. , 2010, Molecular endocrinology.

[50]  G. Perdew,et al.  The aryl hydrocarbon receptor complex and the control of gene expression. , 2008, Critical reviews in eukaryotic gene expression.

[51]  W. Dupont,et al.  Power and sample size calculations. A review and computer program. , 1990, Controlled clinical trials.