title: Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer.
abstract: OBJECTIVE
  Survivin (BIRC5) is a promising tumor biomarker. Conflicting data exist on its prognostic effect in breast cancer. These data may at least be partly due to the manual interpretation of immunohistochemical staining, especially as survivin can be located in both the nucleus and cytoplasm. Quantitative determination of survivin expression using image analysis offers the opportunity to develop alternative scoring models for survivin immunohistochemistry. Here, we present such a model.
  
  
  METHODS
  A breast cancer tissue microarray containing 102 tumors was stained with an anti-survivin antibody. Whole-slide scanning was used to capture high-resolution images. These images were analyzed using automated algorithms to quantify the staining.
  
  
  RESULTS
  Increased nuclear, but not cytoplasmic, survivin was associated with a reduced overall survival (OS; P = 0.038) and disease-specific survival (P = 0.0015). A high cytoplasmic-to-nuclear ratio (CNR) of survivin was associated with improved OS (P = 0.005) and disease-specific survival (P = 0.05). Multivariate analysis revealed that the survivin CNR was an independent predictor of OS (hazard ratio, 0.09; 95% confidence interval, 0.01-0.76; P = 0.027). A survivin CNR of >5 correlated positively with estrogen receptor (P = 0.019) and progesterone receptor (P = 0.033) levels, whereas it was negatively associated with Ki-67 expression (P = 0.04), p53 status (P = 0.005), and c-myc amplification (P = 0.016).
  
  
  CONCLUSIONS
  Different prognostic information is supplied by nuclear and cytoplasmic survivin in breast cancer. Nuclear survivin is a poor prognostic marker in breast cancer. Moreover, CNR of survivin, as determined by image analysis, is an independent prognostic factor.
authors.affiliation: UCD School of Biomolecular and Biomedical Science and UCD School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Donal J
authors.initials: DJ
authors.lastname: Brennan
authors.forename: Elton
authors.initials: E
authors.lastname: Rexhepaj
authors.forename: Sallyann L
authors.initials: SL
authors.lastname: O'Brien
authors.forename: Elaine
authors.initials: E
authors.lastname: McSherry
authors.forename: Darran P
authors.initials: DP
authors.lastname: O'Connor
authors.forename: Ailís
authors.initials: A
authors.lastname: Fagan
authors.forename: Aedín C
authors.initials: AC
authors.lastname: Culhane
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Higgins
authors.forename: Karin
authors.initials: K
authors.lastname: Jirstrom
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Goran
authors.initials: G
authors.lastname: Landberg
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D012044:Regression Analysis; D000077022:Survivin; D046888:Tissue Array Analysis
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin