title: Estrogen promotes breast cancer cell survival in an inhibitor of apoptosis (IAP)-dependent manner.
abstract: The estrogen receptor (ER) is a major prognostic and therapeutic marker that is expressed in nearly 75% of breast tumors. We have previously shown that the presence of inflammatory mediators can alter the genomic function of the estrogen receptor (ER) in a gene specific manner. In particular, 17β-estradiol (E2) works in combination with the pro-inflammatory cytokines to enhance the expression of a number of pro-survival factors, including the Inhibitor of Apoptosis (IAP) family member, cIAP2. Here we confirm that mRNA and protein levels for cIAP2, but not the related family members cIAP1 and XIAP, are highly up-regulated in MCF-7 breast cancer cells by E2 and cytokines. Similar regulation of cIAP2 is evident in other ER positive but not ER negative cell lines. In agreement with its role as a pro-survival factor, cIAP2 is highly expressed in a subset of invasive breast carcinomas but not in normal breast tissue or ductal carcinoma in situ. Antagonizing IAPs with mimetics of SMAC, which is a known endogenous IAP antagonist, or knockdown of IAPs by siRNA led to greater cell death by TNFα and prevented E2 from promoting cell survival. In addition, a SMAC mimetic reversed TNFα resistance in ER positive breast cancer cells that express high levels of endogenous IAPs. In summary, our findings indicate a new mechanism by which E2 allows breast cancer cells to evade cell death and suggest that an antagonist of IAPs may be a potential therapeutic option for a subset of ER positive breast tumors.
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Adina
authors.initials: A
authors.lastname: Stanculescu
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bembinster
authors.forename: Kristina
authors.initials: K
authors.lastname: Borgen
authors.forename: Anna
authors.initials: A
authors.lastname: Bergamaschi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wiley
authors.forename: Jonna
authors.initials: J
authors.lastname: Frasor
mesh_terms: D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D046888:Tissue Array Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D004967:Estrogens; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases