抗激素疗法对于减少三阴性乳腺癌（TNBC）的发病率并不有效，该癌症缺乏雌激素和黄体酮受体。虽然这种侵袭性乳腺癌亚型的病因尚不清楚，但内脏肥胖是前和后绝经期患者的一个强大风险因素。过量沉积的内脏脂肪组织（VAT）促进雌激素受体阴性的乳腺上皮细胞恶性转化的机制目前尚不明确。我们建立了一种新颖的体外恶性转化系统，其中非肿瘤原性的人类乳腺上皮细胞（MCF-10A）在与来自VAT释放的因子培养时可以在软琼脂中生长。这些细胞获得了3D生长的能力，并显示出升高的芳烃羟化酶受体（AhR）蛋白和AhR靶基因，表明AhR活性可能通过VAT来推动恶性转化。AhR是一个配体依赖性转录因子，对外源致癌物和内源色氨酸代谢产物L-色氨酸生成生物学反应。血清色氨酸代谢产物L-色氨酸酮（kynurenine）/色氨酸比值在肥胖患者中升高。在本研究中，我们证明了AhR抑制剂或降低MCF-10A细胞的AhR表达可以预防VAT诱导的恶性转化。具体地说，内源配体结合位点的AhR抑制剂Kyn-101可以抑制VAT引起的细胞转化。质谱分析表明，脂肪细胞代谢色氨酸并释放kynurenine，MCF-10A细胞摄取kynurenine并激活AhR来诱导CYP1B1表达并促进恶性转化。这种新颖的激素受体独立的恶性转化机制暗示在内脏肥胖的背景下以AhR为靶点来预防TNBC。版权所有©2023 Elsevier Inc.发表。

Anti-hormone therapies are not efficacious for reducing the incidence of triple negative breast cancer (TNBC), which lacks both estrogen and progesterone receptors. While the etiology of this aggressive breast cancer subtype is unclear, visceral obesity is a strong risk factor for both pre- and post-menopausal cases. The mechanism by which excessive deposition of visceral adipose tissue (VAT) promotes the malignant transformation of hormone receptor-negative mammary epithelial cells is currently unknown. We developed a novel in vitro system of malignant transformation in which non-tumorigenic human breast epithelial cells (MCF-10A) grow in soft agar when cultured with factors released from VAT. These cells, which acquire the capacity for 3D growth, show elevated aryl hydrocarbon receptor (AhR) protein and AhR target genes, suggesting that AhR activity may drive malignant transformation by VAT. AhR is a ligand-dependent transcription factor that generates biological responses to exogenous carcinogens and to the endogenous tryptophan pathway metabolite, kynurenine. The serum kynurenine to tryptophan ratio has been shown to be elevated in patients with obesity. Herein, we demonstrate that AhR inhibitors or knockdown of AhR in MCF-10A cells prevents VAT-induced malignant transformation. Specifically, VAT-induced transformation is inhibited by Kyn-101, an inhibitor for the endogenous ligand binding site of AhR. Mass spectrometry analysis demonstrates that adipocytes metabolize tryptophan and release kynurenine, which is taken up by MCF-10A cells and activates the AhR to induce CYP1B1 and promote malignant transformation. This novel hormone receptor-independent mechanism of malignant transformation suggests targeting AhR for TNBC prevention in the context of visceral adiposity.Copyright © 2023. Published by Elsevier Inc.