Targeted Therapy: Wave of the Future

Abstract

Understanding Gene Alterations in Human Breast Cancer Gene alterations play an important role in the origin and pathogenesis of human breast cancer. Three broad categories of gene changes that appear to contribute to tumor progression include tumor suppressor genes, repair-mutator genes, and oncogenes. Tumor suppressor genes can be defined as a class of genes whose function is lost as a result of germline or somatic mutation, resulting in tumor development. Repair-mutator genes constitute a subset of the tumor suppressor gene class and are genes involved in DNA repair pathways (such as the DNA mismatch repair genes), whose loss of function likely contributes to cancer via an increased frequency of mutation in other cellular genes involved in growth regulation. Oncogenes are genes directly responsible for cancer progression and often present as altered versions of protooncogenes that are normally involved in control of cell growth and differentiation. In the breast cancer cell, qualitative or quantitative differences are found between the proto-oncogene and its corresponding oncogene. A proto-oncogene can become an oncogene when a mutation in the coding region constitutively activates the biologic activity of the protein product without affecting the total amount of the product. Alternatively, a proto-oncogene can become an oncogene when excess product occurs from amplification (multiple copies) of the gene or from mutation, rearrangement, insertion, or deletion of the regulatory region of the gene. The oncogenes are, in turn, involved in the regulation of a complex series of cyclin-dependent kinases and other cell cycle modulators that determine progression through the cell division cycle. Breast cancer progression is hypothesized to occur by an accumulated series of genetic and phenotypic changes in pathways regulating cell growth. With classic cytogenetic methods and studies of loss of heterozygosity, gene regions identified as commonly rearranged, amplified, or otherwise altered have been commonly detected at chromosome 1, 3, 6, 7, 8, 9, 11, 13, 15, 16, 17, 18, and 20. Application of comparative genomic hybridization has also implicated chromosome 10,12, and 22 in the malignant process. As in most human cancers, the most common genetic abnormality in breast cancer is loss of specific chromosome arms. Loss of heterozygosity analysis of polymorphic DNA markers point to chromosomes and subregions of chromosome arms likely to harbor tumor suppressor genes. Loss of heterozygosity generally allows expression of a recessive mutant in an allele of a tumor suppressor gene by removal of a dominant normal allele, as in the case of p53 expression, for example, in the Li Fraumeni syndrome. The second most common type of cytogenetic alteration in breast cancer appears to be gene amplification. Karyotype analysis and chromosome in situ hybridization approaches such as comparative genomic hybridization or microfluorescent in situ hybridization point to amplified chromosomal loci likely to harbor oncogenes. The initial step in gene amplification may involve the formation of VOLUME 23 d NUMBER 8 d MARCH 1