Curing hereditary breast cancer [Archives:2005/849/Health]

June 9 2005

By Thomas Helleday
In developed countries, breast cancer affects about one in ten women, and in many of these countries the disease is on the increase. But, whatever the reason (or reasons) for the rise in their occurrence, we also know that between 5% and 10% of breast cancers are due to an inherited defect that affects the BRCA1 or BRCA2 genes.

Women carrying a mutated BRCA1 or BRCA2 gene have roughly an 80% risk of developing breast cancer. A mutation in these genes also leads to an increased risk of developing ovarian tumors.

When the BRCA1 and BRCA2 genes were discovered more than a decade ago, there were high hopes for novel and targeted therapies. Disappointingly, no new treatments have yet arisen. As a result, many women with a high level of mutated BRCA1 or BRCA2 genes face the tragic choice of having their breasts and ovaries surgically removed to pre-empt cancer.

Recently, my research group, along with researchers in London, provided some real hope for carriers of mutated BRCA1 or BRCA2 genes. Both research teams describe how the use of a chemical inhibitor can kill tumor cells that have either a BRCA1 or BRCA2 gene defect causing hereditary breast cancer. This new treatment targets only the tumor cells and is unlikely to affect other healthy cells in the body. The discovery could also work to prevent hereditary breast cancer cells from growing into tumors.

The chemical inhibitors used in this treatment target the enzyme polymerase (PARP1), which is normally involved in the repair of DNA single-strand breaks – a common form of spontaneous DNA lesions. Chemical inhibition of the PARP1 protein results in reduced occurrence of these single-strand break repairs.

Unrepaired single-strand breaks are not very toxic to cells. However, these breaks disrupt and damage the DNA when they are copied as DNA replicates. The damage arising when copying the DNA is repaired with recombination, involving the BRCA1 and BRCA2 proteins. But cells with mutated BRCA1 or BRCA2 genes are unable to undergo recombination and are therefore much more sensitive to an increased level of unrepaired single-strand breaks.

The normal cells of women carrying the BRCA1 or BRCA2 mutations can still recombine, because they retain one functional allele)or alternative form)of the gene. Only those cells losing this remaining functional allele of the BRCA1 or BRCA2 gene will become tumors. Thus, only the tumor cells will have a non-functional recombination pathway and rely completely on PARP to repair single-strand breaks before copying the DNA.

In our research, we exploit this requirement to specifically target the BRCA1 or BRCA2-defective cancer cells with inhibitors of PARP. This treatment is unlikely to cause many side effects; prolonged treatments with PARP inhibitors are well tolerated in mice.

We have shown that PARP inhibitors are effective at killing BRCA2-defective breast cancer cells, and that the tumors they cause can fully regress and disappear following treatment with a PARP inhibitor. The next step is to investigate how efficient this treatment is in human patients. We are now initiating clinical trials to determine how efficient these PARP inhibitors are in the treatment of metastasized breast tumors.

But caution is in order. BRCA1 and BRCA2-defective tumors are characterized by a high degree of genetic instability. It is possible that highly metastasized breast tumors might have acquired additional genetic changes causing resistance to treatment with PARP inhibitors. Therefore, we suggest that PARP inhibitors might be more useful in the prophylactic treatment of women carrying the gene responsible for this form of inherited breast cancer.

The reason is simple: cells that have recently lost the functional BRCA1 or BRCA2 allele and that will later grow into tumors will also be unable to undergo recombination. This means that early cancerous cells should be sensitive to PARP inhibitors. However, unlike fully developed tumors, they are not likely to have acquired many genetic changes and are therefore unlikely to have gained resistance to PARP inhibitors.

Treating women carrying BRCA1 or BRCA2 mutations with PARP inhibitors to kill cancer cells before they grow into tumors is a new and hopeful concept in cancer prevention. However, the usefulness of this treatment relies on the fact that PARP1 inhibitors are completely non-toxic to humans. It will also take longer to validate a PARP inhibitor for use as a prophylactic treatment, because the treatment cannot be proven effective in a short time.

Thus, while the use of PARP inhibitors to treat established tumors may be feasible within a few years, we could have to wait at least a decade before a prophylactic treatment for inherited breast cancer is widely available.

Thomas Helleday is a senior lecturer at the University of Sheffield and an Associate Professor at Stockholm University.

Copyright: Project Syndicate, 2005.