乳腺癌是全球女性中最常见的恶性肿瘤之一。终身内源性和外源性的雌激素暴露，以及环境暴露于雌激素类化合物，是乳腺癌发展的最重要风险因素之一。随着乳腺肿瘤的建立，多个通路发生异常。其中之一是芳香族烃受体(AHR)信号通路。AHR是一个与多环芳香族烃和雌激素代谢相关的配体激活型转录因子，在乳腺癌中过度表达。此外，观察到AHR与雌激素受体(ER)的相互作用通路。此外，色氨酸(Trp)降解酶indolamine-2,3-dioxygenase (IDO)和tryptophan-2,3-dioxygenase (TDO)在乳腺癌中过度表达。IDO/TDO催化酪氨酸(KYN)及其他色氨酸衍生物的形成，它们是AHR的配体。一旦KYN激活AHR，它刺激IDO酶的表达，提高KYN的水平，并激活非经典通路来控制乳腺肿瘤中的炎症和免疫抑制。E2、AHR和IDO/TDO/KYN通路之间的相互作用及其对免疫系统的影响组成了乳腺癌的免疫抑制轴。免疫抑制型的E2-AHR-IDO/TDO/KYN轴的潜在调节引起了对抗癌疗法的巨大期望。本文将审查在乳腺癌中产生免疫抑制轴E2-AHR-IDO/TDO/KYN的机制以及作为潜在治疗靶点的当前认识水平。版权所有© 2023。由Elsevier Inc.出版。

Breast cancer is one of the most common malignancies among women worldwide. Estrogen exposure via endogenous and exogenous sources during a lifetime, together with environmental exposure to estrogenic compounds, represent the most significant risk factor for breast cancer development. As breast tumors establish, multiple pathways are deregulated. Among them is the aryl hydrocarbon receptor (AHR) signaling pathway. AHR, a ligand-activated transcription factor associated with the metabolism of polycyclic aromatic hydrocarbons and estrogens, is overexpressed in breast cancer. Furthermore, AHR and estrogen receptor (ER) cross-talk pathways have been observed. Additionally, the Tryptophan (Trp) catabolizing enzymes indolamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are overexpressed in breast cancer. IDO/TDO catalyzes the formation of Kynurenine (KYN) and other tryptophan-derived metabolites, which are ligands of AHR. Once KYN activates AHR, it stimulates the expression of the IDO enzyme, increases the level of KYN, and activates non-canonical pathways to control inflammation and immunosuppression in breast tumors. The interplay between E2, AHR, and IDO/TDO/KYN pathways and their impact on the immune system represents an immunosuppressive axis on breast cancer. The potential modulation of the immunosuppressive E2-AHR-IDO/TDO/KYN axis has aroused great expectations in oncotherapy. The present article will review the mechanisms implicated in generating the immunosuppressive axis E2-AHR-IDO/TDO/KYN in breast cancer and the current state of knowledge as a potential therapeutic target.Copyright © 2023. Published by Elsevier Inc.