Human DNA topoisomerase II-alpha: A new marker of cell proliferation in invasive breast cancer

doi:10.1016/S0046-8177(97)90256-2

Human Pathology

Volume 28, Issue 10, October 1997, Pages 1180-1188

https://doi.org/10.1016/S0046-8177(97)90256-2 Get rights and content

Abstract

DNA topoisomerase II-alpha is the molecular target of doxorubicin, an active drug used in the therapy of breast cancer. From many in vitro studies, it is known that high levels of topo II-alpha expression correlate with drug sensitivity, and low levels of topo 11-alpha correlate with drug resistance. In addition, the enzyme is known to be a marker of cell proliferation in normal tissues. Because the number of proliferating cells in a breast cancer has been shown to be prognostically important, and because doxorubicin is used in the treatment of breast cancer, we hypothesized that the measurement of topo 11-alpha in breast cancer may not only give drug sensitivity information but also may yield important data on cell proliferation. In this study, formalin-fixed, paraffin-embedded tissue from 30 specimens of invasive breast cancer from 20 patients were immunohistochemically stained for topo II-alpha with a mouse monoclonal antibody. For each case, a topo II-alpha index was determined that represents the number of positive-staining tumor cells divided by the total number of tumor cells counted times 100. A similar index was determined for MIB1, a known cell proliferation marker. Each case was also graded according to the modified Bloom-Richardson criteria and evaluated for c-erbB-2 amplification, hormonal status, S-phase fraction, and mitotic index. The topo II-alpha index correlates better with the MIB1 index than with the S-phase fraction or mitotic index. The topo II-alpha expression in breast cancer ranges from low (topo II-alpha index <1) to high (topo II-alpha index = 86). Amplification of cerbB-2 was observed in 4 of 28 cases (14%) but did not correlate with high topo 11-alpha indices. We conclude that measurement of topo II-alpha in invasive breast cancer can be readily performed by immunohistochemical staining, and it gives information on the number of cycling tumor cells. In addition, because the enzyme is the molecular target of doxorubicin, the expression of the enzyme may relate also to the sensitivity or resistance of the tumor to doxorubicin-based chemotherapeutic protocols.

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^☆: Supported by a research educational grant from Pharmacia and Upjohn, San Clemente, CA.

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Original contributionHuman DNA topoisomerase II-alpha: A new marker of cell proliferation in invasive breast cancer☆

Abstract

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Anal Biochem

J Biol Chem

Breast cancer

N Engl J Med

A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors

N Engl J Med

A randomized clinical trial evaluating tamoxifen in the treatment of patients with nodenegative breast cancer who have estrogen-receptor-positive tumors

N Engl J Med

Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer

N Engl J Med

Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer

N Engl J Med

Studies of the HER2/neu proto-oncogene in human breast and ovarian cancer

Science

c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer

N Engl J Med

Her2/neu in node-negative breast cancer: Prognostic significance of overexpression influenced by the presence of in situ carcinoma

J Clin Oncol

Prediction of early course of breast carcinoma by thymidine labeling

Cancer

Prediction of relapse or survival in patients with node-negative breast cancer by DNA flow cytometry

N Engl J Med

Prognostic significance of S-phase fraction in good-risk, node-negative breast cancer patients

J Clin Oncol

Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: Relationship with DNA binding affinity and cytotoxicity

Biochemistry

Characterization and immunological identification of cDNA clones encoding two human topoisomerase isozymes

Biochemical and pharmacological properties of p170 and p180 forms of topoisomerase II

Biochemistry

Altered topoisomerase II-alpha in a drug-resistant small cell lung cancer cell line selected in VP-16

Cancer Res

A novel mutant topoisomerase II-alpha present in a VP-16-resistant human melanoma cell lines has a deletion of alanine 429

Biochemistry

Cytoplasmic localization of a mutant Mr 160,000 topoisomerase II-alpha is associated with the loss of putative bipartite nuclear localization signals in a drug-resistant human lung cancer cell line

Cancer Res

Functional expression of human topoisomerase II-alpha in yeast: Mutations at amino acids 450 or 803 of topoisomerase II-alpha result in enzymes that can confer resistance to anti-topoisomerase II agents

Cancer Res

Expression of topoisomerase II alpha and beta in an adenocarcinoma cell line carrying amplified topoisomerase II alpha and retinoic acid receptor alpha genes

Br J Cancer

Original contribution
Human DNA topoisomerase II-alpha: A new marker of cell proliferation in invasive breast cancer☆

Cytoplasmic localization of a mutant M_r 160,000 topoisomerase II-alpha is associated with the loss of putative bipartite nuclear localization signals in a drug-resistant human lung cancer cell line