title: Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells.
abstract: OBJECTIVE
  Signal transducer and activator of transcription 3 (Stat3) protein is persistently activated in breast cancer and promotes tumor cell survival. To gain a better understanding of the role of constitutive Stat3 signaling in breast cancer progression, we evaluated the expression profile of potential Stat3-regulated genes that may confer resistance to apoptosis.
  
  
  METHODS
  Stat3 signaling was blocked with antisense oligonucleotides in human MDA-MB-435s breast cancer cells and Affymetrix GeneChip microarray analysis was done. The candidate Stat3 target gene Survivin was further evaluated in molecular assays using cultured breast cancer cells and immunohistochemistry of breast tumor specimens.
  
  
  RESULTS
  Survivin, a member of the inhibitor of apoptosis protein family, was identified as a potential Stat3-regulated gene by microarray analysis. This was confirmed in Survivin gene promoter studies and chromatin immunoprecipitation assays showing that Stat3 directly binds to and regulates the Survivin promoter. Furthermore, direct inhibition of Stat3 signaling blocked the expression of Survivin protein and induced apoptosis in breast cancer cells. Direct inhibition of Survivin expression also induced apoptosis. Increased Survivin protein expression correlates significantly (P = 0.001) with elevated Stat3 activity in primary breast tumor specimens from high-risk patients who were resistant to chemotherapy treatment.
  
  
  CONCLUSIONS
  We identify Survivin as a direct downstream target gene of Stat3 in human breast cancer cells that is critical for their survival in culture. Our findings suggest that activated Stat3 signaling contributes to breast cancer progression and resistance to chemotherapy by, at least in part, inducing expression of the antiapoptotic protein, Survivin.
authors.affiliation: Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Gritsko
authors.forename: Ann
authors.initials: A
authors.lastname: Williams
authors.forename: James
authors.initials: J
authors.lastname: Turkson
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Tammy
authors.initials: T
authors.lastname: Bowman
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.forename: Sangkil
authors.initials: S
authors.lastname: Nam
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Eweis
authors.forename: Nils
authors.initials: N
authors.lastname: Diaz
authors.forename: Daniel
authors.initials: D
authors.lastname: Sullivan
authors.forename: Sean
authors.initials: S
authors.lastname: Yoder
authors.forename: Steve
authors.initials: S
authors.lastname: Enkemann
authors.forename: Steven
authors.initials: S
authors.lastname: Eschrich
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Craig A
authors.initials: CA
authors.lastname: Beam
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.forename: Susan
authors.initials: S
authors.lastname: Minton
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Muro-Cacho
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; D000077022:Survivin