Two major forms of genetic alteration in breast cancer are loss of specific chromosome arms and gene amplification. Loss of heterozygosity analysis of polymorphic DNA markers have implicated chromosomes and subregions of chromosome arms that probably harbor tumor suppressor genes [7
]. Nonetheless, in only a few cases have specific genes relevant to allelic loss been identified. Karyotype analysis and chromosome in situ
hybridization approaches, such as comparative genomic hybridization or fluorescent in situ
hybridization, point to amplified chromosomal loci likely to harbor oncogenes, and facilitate loss of heterozygosity studies by identifying regions of the genome that are under-represented in tumors [6
]. These studies have shown that breast cancers are unusual among human tumors because of their great degree of genetic heterogeneity, suggesting that breast cancer in reality results from multiple genetic changes. Although characterization of the many unidentified genes that are relevant to allelic loss and gene amplification will undoubtedly suggest additional gene therapy strategies for breast cancer, current knowledge of a few such targets already offers the possibility of effective intervention.
The genetic heterozygosity of breast cancer may thus predicate gene therapy approaches that are targeted to multiple dysregulated alleles. In this regard, the genetic heterogeneity of breast cancer is reflected in the various oncogenes previously implicated. Genetic alteration involving known oncogenes is restricted to six loci that undergo gene amplification. No known genes, including the ras
family members, have been shown to undergo base mutation or translocation in primary human breast cancer. Gene amplification occurs at the following specific loci at the approximate frequencies indicated: erb
B-2 (chromosome 17q12, 20% of tumors), c-myc
(8p24, 20%), PRAD1/CYD1
(11q13, 15%), the fibroblast growth factor receptors (8p12, 10-15%), BEK
(10q26, 10-15%), and the insulin-like growth factor receptor (IGF) (15q24-25, 2%). It also involves unidentified genes at chromosomes 13q31, 17q22-24, and 20q12-13.2 [19
]. In addition to these, other potential oncogenes that are expressed in the absence of genetic alteration include H-ras
B-1/epidermal growth factor receptor (EGFR), erb
B-3, and others. Thus, a variety of candidate oncogenes have been identified that might be approached via genetic ablation strategies.
With the exceptions of c-myc
(encoding the kinase-associated cyclin D1
), gene amplification in breast cancer commonly involves one of several growth factor receptors, as noted above. Although the signal transduction mechanisms of these diverse molecules are currently under study, it is likely that common elements of the signaling machinery are involved. For example, signaling by p185c-ErbB-2/1(ErbB-2)
utilizes downstream elements such as phospholipase C-γ, phosphatidylinositol 3-kinase, guanosine triphosphatase-activating protein, and the adapter protein SHC [22
]. Gene therapeutic modulation of the basal signal transduction apparatus could therefore prove effective in a majority of breast cancer cases. Thus, despite the molecular heterogeneity, common points of dysregulation can provide a limited set of rational targets.