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HER-2/neu and topoisomerase IIalpha in breast cancer
Tero A H Järvinen1, Edison T Liu
1Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland. blteja@uta.fi
Abstract:
In breast cancer, the predominant genetic mechanism for oncogene activation is through an amplification of a gene. 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 important role in breast cancer growth and progression, HER-2 is also a target for a new form of chemotherapy. Breast cancer patients have been treated with considerable success since 1998 with trastuzumab, a recombinant antibody designed to block signaling through HER-2 receptor. HER-2 has also been implicated in altering the chemosensitivity of breast cancer cells to different forms of conventional cytotoxic chemotherapy, particularly of topoII-inhibitors (e.g., anthracyclines). Topoisomerase IIalpha gene is located just by the HER-2 oncogene at the chromosome 17q12-q21 and is amplified or deleted in almost 90% of the HER-2 amplified primary breast tumors. Recent data suggests that amplification and deletion of topoisomerase IIalpha may account for both relative chemosensitivity and resistance to anthracycline therapy, depending on the specific genetic defect at the topoIIalpha locus. Expanding our understanding of HER-2 amplification also changes its role in the pathogenesis of breast cancer. HER-2 is an oncogene that clearly can drive tumor induction and growth and is also a target for a new kind of chemotherapy, but its function as a marker for chemoselection may be due to associated genetic changes, of which topoisomerase IIalpha is a good example. Moreover, despite potential evidence that genes other than HER-2, such as topoisomerase IIalpha, may be more important predictors of therapeutic response in breast cancer, HER-2 status still has a very significant role in therapeutic selection, mainly as the major criterion for administering trastuzumab in treating breast cancer. Thus, the clinical and therapeutic importance of the HER-2 and topoisomerase IIalpha status to breast cancer management should only increase in the next few years.
Insights
Amplification of the HER-2 oncogene drives breast cancer growth and response to therapies like trastuzumab. Associated genetic changes, particularly in the topoisomerase IIalpha gene, also influence chemotherapy sensitivity and resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The Human Epidermal growth factor Receptor 2 (HER-2) oncogene is frequently amplified in breast cancer, correlating with poor prognosis.
- HER-2 overexpression drives tumor growth and is a key target for therapies like trastuzumab.
- HER-2 status influences breast cancer cell sensitivity to chemotherapy, particularly topoisomerase II inhibitors.
Purpose of the Study:
- To explore the role of HER-2 amplification in breast cancer pathogenesis.
- To investigate the interplay between HER-2 and topoisomerase IIalpha (topoIIalpha) in determining therapeutic response.
- To clarify the clinical significance of HER-2 and topoIIalpha in breast cancer management.
Main Methods:
- Review of existing literature on HER-2 and topoIIalpha in breast cancer.
- Analysis of genetic alterations in HER-2 amplified tumors.
- Correlation of genetic status with clinical outcome and chemosensitivity.
Main Results:
- HER-2 amplification is a primary driver of breast cancer, targeted by trastuzumab.
- Topoisomerase IIalpha gene, located near HER-2, is frequently co-amplified or deleted in HER-2 positive tumors.
- TopoIIalpha alterations may dictate sensitivity or resistance to anthracycline chemotherapy.
Conclusions:
- While HER-2 is crucial for treatment selection (e.g., trastuzumab), associated genetic changes like topoIIalpha status are vital for predicting response to conventional chemotherapy.
- Understanding the combined role of HER-2 and topoIIalpha enhances personalized breast cancer treatment strategies.
- The clinical importance of assessing both HER-2 and topoIIalpha is expected to grow for optimizing breast cancer therapy.