ABSTRACT
Tumor angiogenesis is a critical component of carcinogenesis and metastasis. Admittedly, many factors impact upon the process. We will not attempt to define race in this chapter but will review the current literature reporting the presence of polymorphisms found within certain ethnic groups and their influence on the process of angiogenesis. As we review and analyze data relating to the differences in gene expression which affect angiogenesis pathways within specific racial/ethnic groups we will speculate on the importance of polymorphisms responsible for these genetic variations. We will review the limited data relating to the role of polymorphisms on breast cancer subtypes at diagnosis as well as on prognosis and response to treatment. The role of polymorphisms in differing responses to treatment between ethnic groups continues to be elucidated. We will also discuss findings from current literature analyzing the effect of polymorphisms on the expression and function of proteins constituting the tumor microenvironment. One important aspect that could influence breast cancer outcome between ethnic groups is the interaction of the adipocytokines with their receptors and receptor expression. The effect of the presence of polymorphisms on the expression of these components will be reviewed as well as the effect of polymorphisms on downstream events initiated by ligand/receptor binding including intracellular signaling pathways
2 Genetic Polymorphisms Polymorphisms are gene variants that appear with a frequency of greater than 1% throughout the general population. They occur approximately once every 1,000 base pairs (bps). The most common and most simple
polymorphism is the single nucleotide polymorphism (SNP). Additionally deletions, insertions, duplications and microsatellite repeats can occur with some measure of frequency. SNPs can be classified as either coding or non-coding depending on their placement within the gene. Polymorphisms can lead to changes in phenotype by altering protein structure directly, or they may be in linkage disequilibrium with a functional variant (Syvanen 2001). Polymorphisms in regulatory regions such as the promoter, the 5’/3’ untranslated regions or the splice sites may have an influence on either transcription or mRNA stability (Wagner et al. 2007). The NCBI SNP database lists a total of 12,632,873 human SNPs (12,539,846 validated) (https://www.ncbi.nlm.nih.gov/SNP/snp_summary.cgi)
Angiogenesis, the process of new blood vessel forming from pre-existing vessels, has become a much studied phenomenon in the pathogenesis of cancer. The relationship between the key components of angiogenesis must be exact in order for new vessels to grow. The effect of polymorphisms within the genes regulating angiogenesis and the tumor microenvironment including: hypoxia inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), endothelial nitric oxide synthase (eNOS) (https://www.ncbi.nlm.nih.gov/SNP/snp_summary.cgi), Notch, matrix metalloproteinases, insulin-like growth factor (IGF), leptin and adiponectin are all key components of angiogenesis. The key polymorphisms of these genes reviewed in this chapter are listed in Table 1.
