Victorian researchers have shed light on one of the major causes of breast cancer and have opened the door to developing effective and non-invasive prevention strategies.
Researchers from the Melbourne-based Walter and Eliza Hall Institute of Medical Research (WEHI) have discovered that an existing medication could be used to treat women who are at high risk of breast cancer – a discovery that could potentially open the way for less invasive prevention strategies.
By studying breast tissue from women who carry a faulty BRCA1 gene, popularly known as the Angelina Jolie gene, the researchers were able to pinpoint the cells responsible for cancer development.
The project’s co-leaders, professors Jane Visvader and Geoff Lindeman, began their research nearly 15 years ago thanks to support from the Victorian Breast Cancer Research Consortium, funded by the Victorian Government.
Time hasn’t dulled the optimism of either researcher, with both continuing to look to the future.
“The findings offer hope that this may be a useful breast cancer prevention strategy for the next generation of women—those who are young girls or teenagers now,” says Lindeman.
Professor Visvader explained their research in more detail: “We discovered that the likely precursor cells that give rise to breast cancer in BRCA1 mutation carriers contain a protein called RANK. These RANK-positive cells are important for switching on the growth of breast cells in response to the female hormone progesterone.
“Since RANK-positive breast cells are likely the culprit cells that become cancerous, switching them off could represent a promising strategy for preventing breast cancer.”
This is significant, she explains because inhibitors of the RANK pathway already exist.
Around 25,000 Australian women carry a faulty BRCA1 gene, says Professor Lindeman. These women have up to a 65 per cent risk of developing breast cancer in their lifetime.
If an inhibitor could be used to stop breast tissue mutating into tumours, it could provide a non-surgical option to prevent breast cancer in women with elevated genetic risk.
It is estimated that between 1-in-400 to 1-in-800 Australian women carry a faulty BRCA1 gene and, for them, prevention options are limited.
Professor Lindeman explains the preventative measure some women with the gene will take:
“Some women will opt for a prophylactic [preventive] mastectomy because it is the only truly effective prevention strategy at the present time. Currently, in Australia, about 20 per cent of women opt for this approach.
“What’s really needed is a much less invasive strategy for these young women that delays or even prevents the development of breast cancer.”
A drug that inhibits RANK signalling, called Denosumab, is already approved for clinic-based treatment of osteoporosis and for breast cancer that has spread to the bone. The findings from the WEHI research team suggests that denosumab could be ‘repurposed’ as a breast cancer prevention drug.
“Of course, this question now needs to be addressed through rigorous testing in clinical trials,” says Lindeman.
Working with Denosumab’s developer, Amgen, Lindeman and collaborators are conducting a pilot study at the Royal Melbourne Hospital to test the drug’s effectiveness.
Pleasingly, says Lindeman, “we saw a reduction in breast cell proliferation after Denosumab treatment in the first three BRCA1 mutation carriers treated, so this approach really does look promising.”
“We also showed that it is possible to switch off breast cell growth using other laboratory models. We further discovered that it was possible you to prevent or delay tumour development using a RANK pathway inhibitor in a mouse model.”
The team is now working to complete the pilot clinical trial. The study is exploring the effects of denosumab on breast tissue from BRCA1 and BRCA2 mutation carriers, as well as women who are at high risk due to a strong family history of breast cancer.
The hope is that this approach will be effective—not only for women with the BRCA1 gene—but other women at elevated genetic risk.
Visvader and Lindeman, who began the research in about 15 years ago thanks to Victorian Government support through the Victorian Breast Cancer Research Consortium, are optimistic.
“The findings offer hope that this may be a useful breast cancer prevention strategy for the next generation of women—those who are young girls or teenagers now,” says Lindeman.
