Original articleAllelic imbalance of HER2 variant in sporadic breast and ovarian cancer
Introduction
The HER2 oncogene belongs to the family of receptor tyrosine kinase type I and is strongly involved in breast cancer tumorigenesis. The mechanisms related to HER2 gene amplification, protein overexpression, and activation are complex and still inadequately understood. HER2 overexpression is frequently associated with gene amplification and is found in up to 20–30% of breast and ovarian cancers [1], [2]. At the present time, HER2 amplification is an established prognostic factor in breast cancer, and is associated with several clinico-pathologic features and a decreased survival time [3]. Due to its apparently important role in the genesis of some cancers, HER2 has become an attractive target for novel molecularly targeted therapies, e.g., Trastuzumab therapy [4], [5].
The driving force for transmembrane signaling via receptor tyrosine kinases is the process of ligand-induced receptor dimerization. HER2 is unique among the HER2 family of receptors because it lacks a specific ligand. HER2 serves as a heterodimerization partner for other members of the HER family. These heterodimers are long-lived and further enhance cell signaling. In animal models, a point mutation altering the transmembrane domain of the rat neu gene converts the normal gene into a potent oncogene [6]. A corresponding mutation, however, has not been identified in human tumors.
The sequence analysis of human HER2 has identified a polymorphism in the transmembrane coding region at codon 655 that encodes either for isoleucine (ATC) or valine (GTC). The homo- or heterozygous Val genotype is associated with an increased risk of breast cancer, particularly among younger women with a positive familial history [7], [8], [9]. It is not known how this variant contributes to the risk of developing sporadic breast cancer.
In the study, we examined the relationship of HER2 expression, gene amplification, and the HER2 genotype in sporadic breast and ovarian tumors. All tumors subjected to analysis had corresponding normal tissue available for determining the stem line HER2 genotype and identifying possible alterations in the tumor genotype during tumorigenesis.
Section snippets
Tissue material
The samples came from the well–characterized breast and serous ovarian carcinoma materials whose gene amplification and protein expression status was known from previous studies [10], [11]. Both amplification and/or overexpression-positive and -negative samples were included in this study. For breast and ovarian carcinomas, more than five gene copies per nucleus were regarded as high-level amplifications. Normal DNA availability was also a selection criterion for tumor selection. Twenty-nine
HER2 genotype analysis in breast cancer
The tumor tissue genotypes could be determined in 27 (100%) of the breast tumors and in 22 (81.5%) of the normal breast tissue samples available. The Ile/Val genotype was present in nine (40.9%) of the normal tissue samples and in nine tumor samples (33.3%) (Fig. 1; Table 1). Comparison of the normal and tumor tissue genotypes revealed an additional change of Ile/Val to Val/Val in three of the nine Ile/Val cases. The breast cancer tumors with the Val/Val genotype expressed HER2 and harbored HER2
Discussion
The HER2 proto-oncogene was cloned 20 years ago and its clinical relevance is widely recognized today. HER2 overexpression is detected in various types of human cancer, especially in ovarian and breast cancers. Its overexpression is associated with a poor clinical outcome, particularly in node-positive cases [2], [15]. It has been established that HER2 overexpression is a critical step for the initiation and progression of breast cancer. Some tumors deficient in HER2 amplification show
Acknowledgments
The authors thank Ms. Gynel Arifdshan and Laura Pulli for their skillful technical assistance. This work is supported by grants from the Cancer Society of Finland, Foundation for the Finnish Cancer Institute, Helsinki University Research Grants, and the Sigrid Juselius Foundation.
References (35)
- et al.
HER-2/neu oncogene: prognostic factor, predictive factor and target for therapy
Semin Cancer Biol
(1999) - et al.
Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185
Cell
(1986) - et al.
ERBB” amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma
Gynecol Oncol
(2004) - et al.
Structural requirements for ErbB2 transactivation
Semin Oncol
(2001) - et al.
Human breast cancer: correlation of relapse and survival with amplification of the HER2/neu oncogene
Science
(1987) - et al.
Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer
Science
(1989) - et al.
Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease
J Clin Oncol
(1999) - et al.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
N Engl J Med
(2001) - et al.
Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk
J Natl Cancer Inst
(2000) - et al.
The HER2 I655V polymorphism and risk of breast cancer in women < age 40 years
Cancer Epidemiol Biomarkers Prev
(2003)
The HER2 I655V polymorphism and breast cancer risk in Ashkenazim
Epidemiology
Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population-based study
Clin Cancer Res
Identification of expressed genes by laser-mediated manipulation of single cells
Nat Biotechnol
Germline mutations in the ribonuclease L gene in families showing linkage with HPC1
Nat Genet
Tissue microarrays for high-throughput molecular profiling of tumor specimens
Nat Med
The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells
Oncogene
Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors
Mol Cell Biol
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