title: Estradiol regulates Tumor Necrosis Factor-α expression and secretion in Estrogen Receptor positive breast cancer cells.
abstract: 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.
authors.affiliation: Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Sarah Q
authors.initials: SQ
authors.lastname: To
authors.affiliation: Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Cheung
authors.affiliation: Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia; Environmental and Biotechnology Centre, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
authors.forename: Kyren A
authors.initials: KA
authors.lastname: Lazarus
authors.affiliation: Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia. Electronic address: kevin.knower@princehenrys.org.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Knower
authors.affiliation: Cancer Drug Discovery Laboratory, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Clyne
mesh_terms: D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol
keywords: Breast cancer; ERα; Estradiol; TNFα