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Differential expression of the topoisomerase II alpha and beta genes in human breast cancers
M I Sandri1, D Hochhauser, P Ayton
1Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Abstract:
Topoisomerase II is a key target for several anti-cancer drugs used for breast cancer therapy, including doxorubicin, epirubicin and mitoxantrone. Two isoforms of topoisomerase II (alpha and beta) have been described in human cells which differ in their subcellular localisation, biochemical properties and susceptibility to inhibition by anti-cancer drugs. The relative level of expression of the alpha and beta isoforms may contribute to the degree of tumour responsiveness to different chemotherapeutic agents. To assess the relationship between expression of topoisomerase II isoforms and established prognostic factors and pathological variables, 56 primary breast tumour samples were studied. The expression of the two topoisomerase II genes was apparently not co-ordinately regulated in these tissue samples. There was no relationship between any of the commonly used pathological variables [tumour size, lymph node status, S-phase fraction (SPF)] and the level of expression of topoisomerase II beta mRNA. However, high topoisomerase II alpha gene expression was significantly associated with a high SPF (sign-rank test; P = 0.01). Moreover, the ratio of mRNA levels for topoisomerase II alpha and beta showed a stronger relationship to SPF (median raito 0.62 for tumours with SPF < 10, and 1.64 for SPF > 10; P = 0.0021, sign-rank test). As expected from previous studies, an SPF > 10 was associated with poor overall survival (P = 0.01). Immunohistochemical analysis revealed that topoisomerase II beta was widely distributed ( > 90% positive tumour cells), but that topoisomerase II alpha expression was less widely expressed, with a pattern of expression similar to that of the proliferation-dependent antigen recognised by Ki67. Because topoisomerase II gene expression showed a log-normal distribution, log-transformed data were used in multivariate analysis of relapse-free survival. This showed that lymph node status and topoisomerase II beta mRNA expression were the only significant survival factors (P = 0.001 and 0.05, respectively, with relative risks of 1.3 and 1.8). These results indicate that topoisomerase II alpha, but not beta, expression is dependent upon cellular proliferation status, but that the more widely expressed topoisomerase II beta protein may play a significant role as a target for anti-tumour therapy.
Insights
Topoisomerase II alpha expression correlates with breast cancer proliferation, while Topoisomerase II beta levels predict patient survival. These findings highlight distinct roles for Topoisomerase II isoforms in breast cancer, influencing therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Topoisomerase II (TOP2) is a critical target for breast cancer chemotherapeutics like doxorubicin.
- Two TOP2 isoforms, alpha and beta, exhibit differential localization, biochemical properties, and drug susceptibility.
- Isoform expression levels may influence tumor response to chemotherapy.
Purpose of the Study:
- To investigate the relationship between TOP2 isoform expression and prognostic factors in breast cancer.
- To determine the association of TOP2 alpha and beta mRNA levels with pathological variables and patient survival.
Main Methods:
- Analysis of 56 primary breast tumor samples.
- Quantification of TOP2 alpha and beta mRNA expression.
- Assessment of S-phase fraction (SPF) and lymph node status.
- Immunohistochemical analysis for protein expression.
- Multivariate analysis of relapse-free survival.
Main Results:
- TOP2 alpha gene expression strongly correlated with high S-phase fraction (SPF > 10).
- The ratio of TOP2 alpha/beta mRNA levels was significantly associated with SPF.
- TOP2 beta mRNA expression, along with lymph node status, emerged as significant predictors of relapse-free survival.
- TOP2 alpha expression pattern resembled proliferation markers like Ki67, while TOP2 beta was widely expressed.
Conclusions:
- TOP2 alpha expression is linked to cellular proliferation in breast cancer.
- TOP2 beta protein, widely expressed, may serve as a crucial therapeutic target.
- Distinct roles of TOP2 isoforms in breast cancer progression and survival warrant further investigation for targeted therapies.