Estradiol regulates Tumor Necrosis Factor-α expression and secretion in Estrogen Receptor positive breast cancer cells

The cytokine Tumor Necrosis Factor-alpha is critical to Estrogen Receptor positive breast cancer pathology, stimulating estrogen-biosynthesis pathways and preventing the differentiation of estrogen-producing fibroblasts. High concentrations of TNFalpha are detected in the tumor microenvironment, and infiltrating immune cells are thought to be a major source. This study identifies that TNFalpha is also a tumor-derived factor, expressed in ER+ tumour epithelial cells and regulated by 17-beta-estradiol (E2). Treatment of MCF-7, T47D and ZR-75 breast cancer cells with E2 increased TNFalpha mRNA and protein expression and secretion. This effect was mitigated with the use of ERalpha inhibitors 4-hydroy-tamoxifen and ICI-182780, indicating that E2-mediated TNFalpha induction was via the actions of ERalpha. Chromatin immunoprecipitation reveals ERalpha binding to the TNFalpha promoter upon stimulation with E2. This study demonstrates for the first time a positive feedback loop between estradiol and TNFalpha, critical in maintaining high levels of the hormone within the ER+ breast tumour microenvironment.