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Effects of HER-2/neu on chemosensitivity of tumor cells
Tero A. H. Järvinen1, Edison T. Liu
1Institute of Medical Technology, University of Tampere, Tampere University Hospital, Tampere, Finland
Abstract:
In solid tumors, such as breast and ovarian cancer, the predominant genetic mechanism for oncogene activation is through gene amplification. The HER-2 (also known as ErbB2/c-erbB2/HER-2 / neu) oncogene is the most frequently amplified oncogene in breast cancer and its overexpression is associated with poor clinical outcome. In addition to its role in tumor progression, HER-2 has been implicated in altering tumor cell chemosensitivity to cytotoxic chemotherapy, particularly to anthracyclines. However, sophisticated in vitro studies have recently indicated that HER-2 may not have anything to do with the sensitivity of the cancer cells to cytotoxic drugs. Topoisomerase IIalpha gene is a target gene for many cytotoxic drugs and is located just by the HER-2 at the 17q12-q21. TopoIIalpha amplification and deletion may account for both relative chemosensitivity and resistance to anthracycline-therapy depending on the specific genetic defect at the topoIIalpha locus. Whereas HER-2 is an oncogene that clearly can drive tumor induction and growth, its function as a marker for chemoselection may be due to associated genetic changes in the topoIIalpha gene. Copyright 2000 Harcourt Publishers Ltd.
Insights
Gene amplification of HER-2 oncogene is common in breast cancer. However, its role in chemotherapy sensitivity may be linked to the adjacent Topoisomerase IIalpha gene, not HER-2 itself.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gene amplification is a key mechanism for oncogene activation in solid tumors like breast and ovarian cancer.
- The HER-2 oncogene is frequently amplified in breast cancer, correlating with poor outcomes and influencing chemosensitivity.
- Recent in vitro studies question HER-2's direct role in cancer cell sensitivity to cytotoxic drugs.
Purpose of the Study:
- To investigate the relationship between HER-2 amplification and chemosensitivity in solid tumors.
- To explore the potential role of the Topoisomerase IIalpha gene in mediating sensitivity or resistance to anthracycline chemotherapy.
- To clarify whether HER-2's function as a chemoselection marker is due to its own activity or associated genetic alterations.
Main Methods:
- Analysis of gene amplification in solid tumor samples.
- In vitro studies examining cancer cell sensitivity to cytotoxic drugs.
- Genetic analysis of the Topoisomerase IIalpha locus in relation to HER-2.
Main Results:
- While HER-2 amplification is linked to poor prognosis, its direct impact on chemosensitivity is debated.
- The Topoisomerase IIalpha gene, located near HER-2, is a target for cytotoxic drugs.
- Alterations (amplification/deletion) in Topoisomerase IIalpha may determine sensitivity or resistance to anthracyclines.
Conclusions:
- HER-2's role in driving tumor growth is established.
- The association of HER-2 with chemoselection may be an indirect effect of genetic changes in the nearby Topoisomerase IIalpha gene.
- Topoisomerase IIalpha status, rather than HER-2, might be the critical determinant of anthracycline response.