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

• DOI: 10.1016/j.mce.2014.06.020
• Publication Date: 2014-07-05T15:45:46Z
• Authors: Sarah Q. To; Vanessa Cheung; Kyren A. Lazarus; Kevin C. Knower; Colin D. Clyne
• Keywords: Feedback, Physiological; 0301 basic medicine; Chromatin Immunoprecipitation; 0303 health sciences; Estradiol; Tumor Necrosis Factor-alpha; Estrogen Antagonists; Estrogen Receptor alpha; Epithelial Cells; 3. Good health; Gene Expression Regulation, Neoplastic; Tamoxifen; 03 medical and health sciences; Cell Line, Tumor; 616; Humans; Female; RNA, Messenger; Mammary Glands, Human; Promoter Regions, Genetic; Fulvestrant; Protein Binding; Signal Transduction

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