Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples

Abstract

Recent clinical trials have suggested that patients whose breast tumors overexpress HER2 may derive particular benefit from anthracycline-containing chemotherapy compared to that without anthracycline. It has been proposed that the HER2 gene amplification reported in these tumors might mask an underlying TOP2A gene amplification that occurs frequently and concurrently with HER2 amplification. Topoisomerase II alpha, encoded by TOP2A, is a direct molecular target of anthracycline drug action and is potentially useful as a predictive marker of response to anthracycline therapy for breast cancer. In this study, we examined whether TOP2A gene amplification is an appropriate marker for identifying breast tumors expressing high levels of topoisomerase II alpha. We determined topoisomerase II alpha protein expression by immunohistochemistry in 81 human breast tumors in relation to HER2 and TOP2A gene copy numbers analyzed by fluorescence in situ hybridization, histologic grade, cell proliferation fraction measured by MIB-1 expression, and HER2 protein expression determined by immunohistochemistry. The results showed no correlation between TOP2A gene copy number and topoisomerase II alpha protein expression levels in breast tumors, in contrast to the analogous situation for HER2 gene amplification and HER2 immunohistochemistry. Our results suggest that TOP2A gene amplification in breast tumors does not predict high expression of topoisomerase II alpha protein.

Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer

“…TOP2A copy number alterations were highly predictive of pCR (p=0.0002). However, the target of doxorubicin is the topo2a protein rather than the gene, and there is a lack of correlation between gene status and protein expression [39,49,50], probably because of a posttranscriptional regulation of the topo2a protein. As with the TOP2A gene status, the results of the trials that evaluated the correlation of topo2a protein expression and the response to anthracyclines are contradictory, but these studies presented the same methodological caveats previously mentioned [51][52][53].…”

Assessment of Topoisomerase II α Status in Breast Cancer by Quantitative PCR, Gene Expression Microarrays, Immunohistochemistry, and Fluorescence in Situ Hybridization

“…Interestingly, no association between TOP2A copy number alterations and the expression of the gene was observed, which is in agreement with previous reports. 17,40 Because TOP2A is considered the molecular target of anthracyclines, 3 the predictive value of this gene in patients with breast cancer has been widely studied. Several retrospective studies [12][13][14][15][16] have shown that ERBB2-positive tumors are rather sensitive to anthracyclines.…”

Triple-negative breast cancer exhibits a favorable response to neoadjuvant chemotherapy independent of the expression of topoisomerase IIα

“…Notably, the target of anthracycline is the topoisomerase Ⅱα protein as opposed to the gene, and it is known that there is a lack of correlation between gene status and protein expression (28)(29)(30). Proliferation signals can lead to overexpression of the topoisomerase Ⅱα protein independently of the TOP2 gene status (29,31).…”