Deletions of Genes

Researchers are increasingly aware that mutations resulting in loss of function play an important role in the pathogenesis of human malignancies. Deletion of one allele, measured by loss of heterozygosity for restriction fragment length polymorphism, is thought to unmask mutations in the corresponding normal allele. Thus, it is thought that recessive oncogenes are located in chromosomal regions showing a high incidence of allele loss.

In breast cancer, investigators report nonrandom loss of heterozygosity for a number of chromosomal loci. The frequency of loss of heterozygosity ranged from approximately 50 percent for chromosome 17p, to 20 to 30 percent for regions on chromosomes 1q, 3p, 11p, 13q, 17q, and 18q. Moreover, it has been suggested that deletions at several loci tend to occur within the same tumors.

At some of the deleted chromosomal loci, researchers have tentatively identified the recessive oncogene involved. The target for loss on chromosome 13q is thought to be the Rb gene, which was originally isolated as the recessive oncogene that causes retinoblastoma. The Rb gene encodes a protein that is thought to be involved in cell cycle regulation. The region deleted on chromosome 17p includes the p53 gene, which encodes a protein that binds to DNA as a homodimer. In vivo, it may function by binding to and thereby inactivating the suppressor gene products.

RESEARCH MODELS

To address the basic biological questions in the relationship of breast cancer and oral contraceptives, appropriate model systems need to be developed. A recurrent issue in biological research is whether findings in studies of subprimates are predictive of similar findings in humans. Animal models (see Appendix D) have been valuable in studies of breast cancer; in both rodents and dogs, investigators have shown that estrogens can increase the rate of mammary cancer. However, there may be fundamental differences in overall endocrine physiology among various species that preclude direct extrapolation of data from animal models to humans. For example, one pituitary factor, prolactin, is necessary for production of estrogen-induced tumors in mice, whereas a related but different pituitary factor, growth hormone, serves the same function in beagle dogs (see Appendix D). Thus, it is possible that species-specific effects of exogenous steroids such as oral contraceptives will be of primary importance with regard to induction of mammary cancers.



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