[35] Analysis of cancer gene functions through gene inhibition with antisense oligonucleotides

Functional analysis of human cancer susceptibility genes has been greatly facilitated by the use of gene inhibition methods, including homologous recombination in mice and antisense methodologies in human cells. Although homologous recombination has clear-cut advantages over antisense inhibition methods in mouse experimental models, antisense oligonucleotide approaches continue to serve as a rapid and important means of gene inhibition in human cell lines and are of great importance for the study of poorly conserved genes with different functions between the mouse and the human. Breast cancer susceptibility genes are examples of genes with different functions in mouse versus human model systems. Mouse breast cancer 1 (BRCA1) is only 57% homologous to human BRCA1, and BRCA1 functions differently in the two systems. BRCA1 is a powerful growth suppressor in both yeast and human systems but is required for cellular proliferation during mouse development. Humans heterozygous for BRCA1 mutations develop breast cancer early in life, but mice heterozygous for BRCA1 mutations do not develop cancers. Well-described differences in deoxyribonucleic acid (DNA) repair between mouse and human cells complicate the ability to extrapolate results from mouse models to patients. Mouse and human cells show differences in the amount of damage sustained per given DNA-damaging dose in the kinetics of DNA repair and in cellular survival at a given dose of a DNA-damaging agent. BRCA2 is also poorly conserved between the mouse and the human, although some clear functional similarities have been described.