Topoisomerase IIalpha expression in breast cancer: correlation with outcome variables.
Topoisomerase IIalpha (topo IIalpha) plays a key role in DNA replication and is a target for multiple chemotherapeutic agents. In breast cancer, topo II expression has been linked to cell proliferation and HER2/neu protein overexpression. However, its relationship with outcome variables is not well established. Formalin-fixed, paraffin-embedded primary breast cancers from 184 women (mean age, 60 years) were stained for topo II by automated immunohistochemistry. A topo II expression index (TI) was determined by counting the number of positive cells per high-power field and calculating an overall mean number of positive cells per high-power field. Tumors with a TI of more than 1 were considered positive, and those with a TI of 1 or less were considered negative. A cell proliferation index was determine d by automated immunohistochemistry using the MIB-1 antibody in an identical technique. HER-2/neu gene amplification (HER-2 amp) was determined by automated fluorescence in situ hybridization using the Ventana unique sequence probe. Fifty-nine (32%) of the tumors had a TI greater than 1. On univariate analysis, increased topo II expression correlated with decreased patient survival (p = .001), advanced tumor stage (p = .034), lymph node metastasis (p = .018), and HER-2 amp (p = .016). Tumor stage (p < .0001), node-positive status (p < .0001), tumor grade (p = .025), HER-2 amp (p < .0001), and MIB-1 overexpression (p = .002) also correlated with survival on univariate analysis. Topo II expression did not correlate with tumor size, grade, estrogen receptor/progesterone receptor status, or disease recurrence. On multivariate analysis, stage (p < .0001), lymph node metastasis (p < .0001), and tumor grade (p = .002) all independently predicted disease-related death. Increased topo II expression is associated with an aggressive form of breast cancer featuring HER-2 amp and predicts disease-related death, lymph node metastasis, and advanced tumor stage.
Depowski
P L
PL
Department of Pathology, Albany Medical College, New York 12208, USA.
Rosenthal
S I
SI
Brien
T P
TP
Stylos
S
S
Johnson
R L
RL
Ross
J S
JS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm; D034961:Antigens, Nuclear; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis*; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007527:Isoenzymes / Q000096:biosynthesis*; D019394:Ki-67 Antigen; D008207:Lymphatic Metastasis; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000032:analysis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D016019:Survival Analysis
D000951:Antigens, Neoplasm; D034961:Antigens, Nuclear; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone