By Kyle Matchett, Queen’s University Belfast
Angelina Jolie made the decision to have a double mastectomy after discovering she carried a faulty copy of the hereditary gene BRCA1 and was told she had an 87% chance of developing breast cancer. Jolie was a high-profile case, but many other women face this very difficult dilemma.
Women who inherit a faulty copy of the breast cancer gene BRCA1 have a 55-65% lifetime chance of developing breast cancer, compared with about 7% in average women in the developing world. The risk of ovarian cancer is also increased by about 40%.
Although a damaged copy of BRCA1 only accounts for about one in 50 of the breast cancer diagnoses each year, women who have this genetic fault often face a decision: whether or not to have surgery to remove their breasts and/or ovaries. Many factors will be considered such as her age, whether there is a family history of hereditary cancer and whether she is planning to have children, but for many who don’t want to run the risk of developing cancer, surgery is currently the only treatment available.
DNA damage caused by oestrogen
Although women with inherited BRCA1 faults have this mistake in every cell in their body, they mainly develop breast and ovarian cancers. This has been of major interest to researchers since BRCA1 was discovered in 1994. In a recent study, published in Cancer Research, we found evidence that oestrogen is the driving factor behind these cancers and our finding could pave the way for a new therapy that leads to fewer preventative surgeries.
We found that oestrogen and oestrogen metabolites (created when natural oestrogen breaks down) cause a severe type of damage to DNA called double strand breaks. The accumulation of this type of damage often leads to genetic mutations and cancer. It is interesting because although oestrogen caused these breaks in both normal and defective BRCA1 cells, it was the defective cells that couldn’t fix the damage.
It is already known that BRCA1 is very important in the repair of double strand breaks. But the damage driven by the oestrogen metabolites was so severe to the faulty BRCA1 cells that it caused dangerous changes in the cell’s chromosomes (DNA bundles), which often leads to cancer development over time.
In addition to this, we also discovered that BRCA1 regulates the levels of some key enzymes that convert oestrogen into the toxic oestrogen metabolites. Cells with faulty BRCA1 had lost the control of these enzymes, meaning their level was increased and more oestrogen metabolites were being produced. This led to more damage that wasn’t being repaired in these BRCA1 faulty cells.
Taken together, the research suggests that exposure to oestrogen and its subsequent metabolism in defective BRCA1 breast cells can drive DNA damage and instability, an early event in breast cancer development.
Potential in reversible drugs
Our research also suggests that suppression of oestrogen production may be an exciting therapeutic option. One US trial is currently enrolling postmenopausal women for treatment with an aromatase inhibitor, a drug which inhibits production, to prevent breast cancer in patients carrying a BRCA1 mistake. The trial is also testing this for faults in another gene called BRCA2 which carries a 45% risk of developing breast cancer and 15% risk of developing ovarian cancer.
Our results would support this approach. However, these inhibitor drugs would not be suitable for premenopausal women, in whom most BRCA1-linked cancers develop, because in these women oestrogen is produced in the ovaries in a process that doesn’t involve aromatase – a key enzyme that helps the body produce oestrogen. There is, however, a group of drugs called luteinizing hormone-releasing hormone (LHRH) agonists, which cause a reversible suppression of oestrogen production in the ovaries and which are currently used to treat women with other oestrogen-dependent premenopausal cancers. These drugs could be effective in premenopausal women with the faulty BRCA1 gene who have chosen not to undergo preventative surgery.
This could be an opportunity because instead of major surgery, we could use drugs that are already available to chemically reduce oestrogen production in women. It also has the potential to “pause” treatment for women to have children, if desired, before resuming treatment. Our group plans to launch a clinical in the next 12 months to test this approach as a novel, reversible treatment.
Kyle Matchett received funding from Cancer Research UK