title: Correlation between topoisomerase-IIalpha gene amplification and protein expression in HER-2 amplified breast cancer.
abstract: Topoisomerase-IIalpha (topo-II) is a molecular target for topo-II inhibitors, which makes it a potential predictive marker of responsiveness to these agents. We aim to correlate topo-II gene and protein status on 103 HER-2 amplified breast cancer samples. Paraffin-embedded blocks were screened by FISH for topo-II gene amplification (topo-II: CEP17 ratio >/=1.5; triple probe by Vysis inc.) and analyzed by IHC for topo-II protein expression (continuous variable; clone KiS1) and Ki-67 (positive if >25% of stained cells; clone MIB-1). Topo-II gene amplification was observed in 36.9% (38/103) of the HER-2 amplified study population. HER-2 amplification level (e.g. copy number) was not shown to be predictive for topo-II amplification. The median percentage of topo-II positively stained cells by IHC for topo-II non-amplified and amplified cases were 5% and 10%, respectively. A weak but significant correlation was observed between topo-II gene amplification level and percentage of positively stained cells (Spearman's ranks correlation coefficient of 0.23, p=0.02), the observed correlation being higher in patients with positive staining for Ki-67. Contrary to HER-2, where gene amplification is almost always correlated with protein overexpression in breast cancer, topo-II gene amplification apparently does not always lead to protein overexpression, at least when the latter is evaluated by IHC. Other factors, specifically the tumor proliferation status, may interfere with the topo-II protein status. Although the great majority of topo-II gene aberrations occur in HER-2 positive tumors, the level of HER-2 amplification does not predict for topo-II amplification.
authors.affiliation: Translational Research Unit, Jules Bordet Institute, Boulevard de Waterloo 125, 1000 Brussels, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Durbecq
authors.forename: C
authors.initials: C
authors.lastname: Desmed
authors.forename: M
authors.initials: M
authors.lastname: Paesmans
authors.forename: F
authors.initials: F
authors.lastname: Cardoso
authors.forename: A
authors.initials: A
authors.lastname: Di Leo
authors.forename: M
authors.initials: M
authors.lastname: Mano
authors.forename: G
authors.initials: G
authors.lastname: Rouas
authors.forename: J-Y
authors.initials: JY
authors.lastname: Leroy
authors.forename: C
authors.initials: C
authors.lastname: Sotiriou
authors.forename: M
authors.initials: M
authors.lastname: Piccart
authors.forename: D
authors.initials: D
authors.lastname: Larsimont
mesh_terms: D000951:Antigens, Neoplasm; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D002277:Carcinoma / Q000235:genetics* / Q000503:physiopathology*; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007527:Isoenzymes; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*
chemical_list: D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C000618811:TOP2A protein, human