Aryl hydrocarbon receptor-ligand hexachlorobenzene promotes immunosuppression leading to mammary tumor growth and metastasis in a HER2-positive syngeneic mouse model

IF 4.2 3区环境科学与生态学 Q2 ENVIRONMENTAL SCIENCES

Environmental toxicology and pharmacology Pub Date : 2025-08-18 DOI:10.1016/j.etap.2025.104796

Lorena V. Zárate , Jorge A. Peña Agudelo , Noelia V. Miret , Alejandro J. Nicola Candia , Melanie Pérez Kϋper , Carolina A. Pontillo , Florencia A. Chiappini , Marianela Candolfi , Andrea S. Randi

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引用次数: 0

Abstract

Pesticide exposure has been established as a risk factor for breast cancer. Hexachlorobenzene (HCB) is an aryl hydrocarbon receptor (AhR) ligand. Mice bearing LM3 HER2(+) breast tumors were exposed to HCB (35 and 15 days). Tumor growth and lung metastases were evaluated, and key molecules were analyzed by western blot, immunofluorescence and RT-qPCR. Splenic and tumor infiltrating lymphocytes (TILs) were quantified by flow cytometry. Results showed that HCB (35 days) accelerates tumor growth and promotes lung metastases development. HCB upregulates AhR, CYP1A2, IDO1, COX-2 and VEGF expression. The pesticide reduces ERβ and increases GPER levels. Exposure to HCB decreases the content of CD8 + and regulatory T cells in the spleen and antigen-presenting cells in the tumor, without changes in TILs. HCB (15 days) suppresses CD4 + and CD8 + infiltration in tumors. Our findings indicate that HCB facilitates tumor progression in HER2(+) breast cancer, involving the dysregulation of ERs and pro-angiogenic factors. Likewise, AhR overexpression could be modulating the anti-tumor immune response, inducing immunosuppression.

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芳烃受体配体六氯苯在her2阳性小鼠模型中促进免疫抑制导致乳腺肿瘤生长和转移

农药暴露已被确定为乳腺癌的一个危险因素。六氯苯（HCB）是一种芳烃受体（AhR）配体。携带LM3 HER2（+）乳腺肿瘤的小鼠暴露于HCB（35天和15天）。采用western blot、免疫荧光和RT-qPCR分析关键分子，评估肿瘤生长和肺转移情况。流式细胞术定量脾淋巴细胞和肿瘤浸润淋巴细胞（TILs）。结果显示，HCB （35 d）加速肿瘤生长，促进肺转移发展。HCB上调AhR、CYP1A2、IDO1、COX-2和VEGF的表达。农药降低ERβ并增加GPER水平。暴露于HCB会降低脾脏中CD8 + 和调节性T细胞以及肿瘤中抗原提呈细胞的含量，而TILs没有变化。HCB（15天）抑制肿瘤中CD4 + 和CD8 + 浸润。我们的研究结果表明，HCB促进了HER2（+）乳腺癌的肿瘤进展，涉及er和促血管生成因子的失调。同样，AhR过表达可能调节抗肿瘤免疫反应，诱导免疫抑制。

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来源期刊

Environmental toxicology and pharmacology 医学-毒理学

CiteScore

7.00

自引率

4.70%

发文量

185

审稿时长

34 days

期刊介绍： Environmental Toxicology and Pharmacology publishes the results of studies concerning toxic and pharmacological effects of (human and veterinary) drugs and of environmental contaminants in animals and man. Areas of special interest are: molecular mechanisms of toxicity, biotransformation and toxicokinetics (including toxicokinetic modelling), molecular, biochemical and physiological mechanisms explaining differences in sensitivity between species and individuals, the characterisation of pathophysiological models and mechanisms involved in the development of effects and the identification of biological markers that can be used to study exposure and effects in man and animals. In addition to full length papers, short communications, full-length reviews and mini-reviews, Environmental Toxicology and Pharmacology will publish in depth assessments of special problem areas. The latter publications may exceed the length of a full length paper three to fourfold. A basic requirement is that the assessments are made under the auspices of international groups of leading experts in the fields concerned. The information examined may either consist of data that were already published, or of new data that were obtained within the framework of collaborative research programmes. Provision is also made for the acceptance of minireviews on (classes of) compounds, toxicities or mechanisms, debating recent advances in rapidly developing fields that fall within the scope of the journal.