Researchers Hope Function of BRCA1 Gene Holds Key to New Treatments

New knowledge about the normal function of the BRCA1 gene, various mutationsof which have been shown to cause breast and ovarian cancers, may helpresearchers develop treatments for both hereditary and sporadic disease.Jeffrey T. Holt, MD, professor of cell biology and pathology at VanderbiltUniversity School of Medicine in Nashville, discussed ongoing researchat the second International Conference on Genetics and the Environment,jointly sponsored by Strang Cancer Prevention Center and Cornell UniversityMedical College.

Dr. Holt reported that the wild-type BRCA1 gene inhibits the growthof sporadic breast and ovarian cancer cell lines in vitro and suppressesgrowth of established breast and ovarian tumor models in nude mice. Itappears, therefore, that the normal gene functions as a growth inhibitorand tumor suppressor, he said, explaining that the further observationthat mutant BRCA1 genes do not inhibit growth or suppress tumors providesadditional evidence. This is the first direct evidence that the gene inhibitsbreast and ovarian cancer at the cellular level, he said, and that thiseffect is not limited to hereditary disease. The gene may have other functionsyet to be discovered, he added.

Potential Therapeutic Strategies

Dr. Holt explained that a full understanding of how the mutation producescancer may aid in the development of therapeutic strategies. One focusof inquiry is BRCA1 mRNA. Dr. Holt's group observed that although the BRCA1gene is rarely mutated in sporadic breast or ovarian cancer, levels ofBRCA1 mRNA and protein are markedly decreased in the majority of sporadiccancers. "This suggests that hereditary and sporadic breast cancershare common genetic themes, and that treatments aimed at increasing levelsof BRCA1, and possibly BRCA2, may be useful for both hereditary and sporadiccancers," he said.

Gene therapy that delivers nonmutated BRCA1 to the tumor employing aretroviral vector may be able to suppress tumor growth. It did so in nudemice, and a phase I trial of a retroviral vector expressing BRCA1 has recentlybeen completed, with promising results, Dr. Holt reported. In the trial,12 patients with stage III or IV ovarian cancer received four daily intraperitonealinfusions of the vector. Ovarian tumors were selected as the target because"this is an instance where a multiplicity of infection can be achieved,"he said.

The major toxicity was peritonitis, but Dr. Holt said it was less thanthat observed in the nude mice. Although there is uptake of the retrovirusby normal cells, he explained, they do not transduce at the same rate ascancer cells when infected with the retrovirus, and thus, there appearsto be no integration of the retrovirus in nonmalignant cells.

The work is in its earliest stages, Dr. Holt said, acknowledging thatas therapy it represents only a short-term solution, of possible valueto patients who cannot wait for more refined gene therapy strategies. "Itprovides a proof of principles," he said, asserting that its greatestvalue is as a model for the development of new drugs and other treatmentstrategies in breast and ovarian cancer, as well as other cancers for whicha functionally mutated gene has been identified.