We expect that the analyses of these animals will provide insights into the roles of these genes in tumour development. For example, many different tumors have been found to display anomalies in the genome suggestive of defects in DNA mismatch repair. A component of the DNA mismatch repair machinery, hMSH2, has recently been linked to cancer susceptibility in humans. We have generated MSH2-deficient mutant mice and have discovered that they spontaneously develop tumours early in life. These mice can now serve as a model for the study of tumorigenesis, carcinogens and anti-cancer agents.
Tumour suppressors are another important genetic link to cancer.
Mutations of the dominant genes BRCA1 and BRCA2 have been found to confer a greatly increased risk of breast and ovarian cancer. Recent findings suggest that the wild type BRCA1 gene product may operate as a negative regulator of mammary epithelial cell growth. It is postulated that mutations resulting in altered BRCA1 expression may result in tumorigenesis. However, mice with homozygous mutations of either BRCA1 or BRCA2 die at an early stage of embryonic development with an apparent defect in cellular proliferation. PTEN-deficient cells are resistant to agents inducing apoptosis, becoming immortal and thus susceptible to acquiring additional mutations that lead to tumorigenesis.