Mammary hydroxylated oestrogen activates the NLRP3 inflammasome in tumor-associated macrophages to promote breast cancer progression and metastasis

Background: An imbalance of oestrogen homeostasis and an inflammatory tumor microenvironment (TME) are vital risk factors for the progression and metastasis of breast cancer. Methods: The liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantitative analysis method for oestrogen active substances was used to detect the levels of oestrogen and its metabolites of 238 clinical serum samples, 6 clinical malignant breast cancer tissues and their corresponding non-tumor adjacent tissues and MMTV-PyMT mice mammary tissues. In vitro and in vivo experiments were conducted to investigate the correlation between oestrogen and tumor-associated macrophages (TAMs) and the role and mechanism of the NLRP3 inflammasome activated by oestrogen in promoting breast cancer progression and metastasis. Results: Results of the present study demonstrated that tumor-associated macrophages (TAMs) were the main population of immune cells present in the breast TME. Thus, TAM-dependent tumor metastasis may be triggered by hydroxylated oestrogen via NOD-like receptor thermal protein domain associated protein 3 (NLRP3), inflammasome activation and IL-1β production. Mechanistically, TAM-derived inflammatory cytokines induced the expression of matrix metalloproteinases in breast tumor cells, leading to breast tumor invasion and metastasis. Collectively, these results revealed a previously unknown role of hydroxylated oestrogen in the reprogramming of the TME via NLRP3 inflammasome activation in TAMs. These mechanisms may facilitate breast cancer cell proliferation, migration and invasion. Conclusions: The disorder of oestrogen metabolism in the breast, especially the abnormal elevation of hydroxylated oestrogen, may be a risk factor for the metastasis of breast tumors. Hydroxylated oestrogens act on TAMs to induce the generation of an inflammatory microenvironment in breast tumors, thereby regulating the progression of breast cancer.