乳腺癌仍然是癌症相关死亡的主要原因之一。雌激素稳态失衡和炎症肿瘤微环境（TME）是乳腺癌进展和转移的重要危险因素。在这里，我们发现乳腺癌患者和转基因 MMTV-PyMT 乳腺癌小鼠模型中的雌激素稳态均被破坏，并且这些患者和小鼠的乳腺组织中积累了显着水平的羟基化雌激素。我们还观察到肿瘤相关巨噬细胞 (TAM) 是乳腺 TME 中存在的主要免疫细胞群。羟基化雌激素可通过 NLRP3 炎性体激活和 IL-1β 产生来触发 TAM 依赖性肿瘤转移。从机制上讲，TAM衍生的炎症细胞因子诱导乳腺肿瘤细胞中基质金属蛋白酶（MMP）的表达，导致乳腺肿瘤侵袭和转移。从概念上讲，我们的研究揭示了羟基化雌激素在通过 TAM 中 NLRP3 炎性体激活对 TME 进行重编程中的先前未知的作用，最终促进乳腺癌细胞增殖、迁移和侵袭。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Breast cancer remains one of the primary causes of cancer-related death. An imbalance of oestrogen homeostasis and an inflammatory tumor microenvironment (TME) are vital risk factors for the progression and metastasis of breast cancer. Here, we showed that oestrogen homeostasis was disrupted both in breast cancer patients and in a transgenic MMTV-PyMT mouse model of breast cancer, and significant levels of hydroxylated oestrogen accumulated in the mammary tissues of these patients and mice. We also observed that tumor-associated macrophages (TAMs) were the main population of immune cells present in the breast TME. TAM-dependent tumor metastasis could be triggered by hydroxylated oestrogen via NLRP3 inflammasome activation and IL-1β production. Mechanistically, TAM-derived inflammatory cytokines induced the expression of matrix metalloproteinases (MMPs) in breast tumor cells, leading to breast tumor invasion and metastasis. Conceptually, our study reveals a previously unknown role of hydroxylated oestrogen in the reprogramming of the TME via NLRP3 inflammasome activation in TAMs, which ultimately facilitates breast cancer cells proliferation, migration, and invasion.Copyright © 2024 Elsevier B.V. All rights reserved.