New knowledge about the normal function of the BRCA1 gene, various mutations
of which have been shown to cause breast and ovarian cancers, may help
researchers develop treatments for both hereditary and sporadic disease.
Jeffrey T. Holt, MD, professor of cell biology and pathology at Vanderbilt
University School of Medicine in Nashville, discussed ongoing research
at the second International Conference on Genetics and the Environment,
jointly sponsored by Strang Cancer Prevention Center and Cornell University
Dr. Holt reported that the wild-type BRCA1 gene inhibits the growth
of sporadic breast and ovarian cancer cell lines in vitro and suppresses
growth of established breast and ovarian tumor models in nude mice. It
appears, therefore, that the normal gene functions as a growth inhibitor
and tumor suppressor, he said, explaining that the further observation
that mutant BRCA1 genes do not inhibit growth or suppress tumors provides
additional evidence. This is the first direct evidence that the gene inhibits
breast and ovarian cancer at the cellular level, he said, and that this
effect is not limited to hereditary disease. The gene may have other functions
yet to be discovered, he added.
Potential Therapeutic Strategies
Dr. Holt explained that a full understanding of how the mutation produces
cancer may aid in the development of therapeutic strategies. One focus
of inquiry is BRCA1 mRNA. Dr. Holt's group observed that although the BRCA1
gene is rarely mutated in sporadic breast or ovarian cancer, levels of
BRCA1 mRNA and protein are markedly decreased in the majority of sporadic
cancers. "This suggests that hereditary and sporadic breast cancer
share common genetic themes, and that treatments aimed at increasing levels
of BRCA1, and possibly BRCA2, may be useful for both hereditary and sporadic
cancers," he said.
Gene therapy that delivers nonmutated BRCA1 to the tumor employing a
retroviral vector may be able to suppress tumor growth. It did so in nude
mice, and a phase I trial of a retroviral vector expressing BRCA1 has recently
been completed, with promising results, Dr. Holt reported. In the trial,
12 patients with stage III or IV ovarian cancer received four daily intraperitoneal
infusions of the vector. Ovarian tumors were selected as the target because
"this is an instance where a multiplicity of infection can be achieved,"
The major toxicity was peritonitis, but Dr. Holt said it was less than
that observed in the nude mice. Although there is uptake of the retrovirus
by normal cells, he explained, they do not transduce at the same rate as
cancer cells when infected with the retrovirus, and thus, there appears
to be no integration of the retrovirus in nonmalignant cells.
The work is in its earliest stages, Dr. Holt said, acknowledging that
as therapy it represents only a short-term solution, of possible value
to patients who cannot wait for more refined gene therapy strategies. "It
provides a proof of principles," he said, asserting that its greatest
value is as a model for the development of new drugs and other treatment
strategies in breast and ovarian cancer, as well as other cancers for which
a functionally mutated gene has been identified.