BRCA1 and BRCA2 focused breast and ovarian cancer research
About the BRCA1 and BRCA2 mutation
Breast cancer is the most common cancer affecting women in Australia with 134,000 new cases diagnosed each year. On average, 37 women are diagnosed with the disease every day. Around 12 per cent of women will develop breast cancer in their lifetime.
Ovarian cancer is the second most commonly diagnosed gynaecological cancer. The majority of the 1,500 Australian women diagnosed with ovarian cancer each year are diagnosed with advanced stage disease. On average, four Australian women are diagnosed with ovarian cancer every day.
The BRCA1 and BRCA2 genes are key tumour suppressor genes that are normally expressed in breast or ovarian tissue, where they work to repair DNA damage and prevent tumours from forming. In women with a mutation in the BRCA1 gene, this DNA damage cannot be repaired, meaning they are at a much greater risk of developing breast and ovarian cancer.
Women with a mutation in the BRCA1 gene are at a higher lifetime risk of developing breast cancer (30 – 65 per cent) and ovarian cancer (20 per cent), often at an early age. While regular screening can detect breast cancer at an early stage and survival rates for breast cancer have improved, there is still a pressing need to develop effective preventative strategies for women who are at a high risk of inherited disease.
Critically, for a fifth of women with BRCA1 or BRCA2 mutations, genetic based tests cannot currently predict if they will develop breast cancer. The mutations for this group are too rare and it is still unknown whether these mutations impact tumour development. Understanding the impact of these mutations may prevent unnecessary surgical intervention.
Research is the way to help. Better understanding of how tumours originate, grow and spread results in better ways to prevent, detect and treat breast and ovarian cancer in women with a BRCA1 mutation.
Our BRCA1 and BRCA2 cancer research focuses on
- Understanding how the female hormone oestrogen contributes to BRCA1-associated breast cancer
- How blocking the cancer-promoting effects of oestrogen could provide an alternative to mastectomy in high-risk women with a BRCA1 mutation
- A novel screening test for ovarian cancer in women with BRCA1 and BRCA2 mutations
- The development of new ways to characterise the impact of rare BRCA1 mutations on tumour development.
Key areas of investigation
1. Oestrogen metabolism and BRCA1-associated breast cancer
Women who harbour a mutation in BRCA1 have an increased risk of developing breast cancer. BRCA1 normally repairs damaged DNA but when mutated, BRCA1 loses this activity – increasing the chances that naturally-occurring DNA damage goes unrepaired, leading to cancer.
BRCA1 is present throughout the body but it is unclear why cancers related to it are largely confined to the breast. The female hormone oestrogen is thought to be involved, since breast tissue is highly sensitive to this hormone. However, once established, most BRCA1-associated breast cancers are oestrogen-independent.
Oestrogen can be converted to other compounds in the breast. Some of these compounds attach to DNA and cause damage. With no BRCA1 activity to repair this damage, this may be one reason why BRCA1 cancers are most common in the breast.
We are seeking to discover if blocking the production of these toxic oestrogen metabolites can protect against breast cancer development when BRCA1 is mutated. We are also using the Human Variome Project to determine if natural variation in genes involved in oestrogen metabolism contributes to breast cancer risk in BRCA1 mutation carriers.
Understanding pathways of oestrogen metabolism may lead to new BRCA1 prevention strategies, as an alternative to mastectomy.
Cancer Drug Discovery
Florey Institute, Melbourne
St Vincent’s Institute, Melbourne
Duke University, USA
Cancer Council VIC
2. Early detection test – reducing the need for surgery
Women with hereditary mutations in the BRCA1 or BRCA2 genes have an elevated risk of developing ovarian cancers. Prophylactic surgery to remove the ovaries and fallopian tubes (salpingo-oophorectomy) can reduce the risk of developing ovarian cancer by up to eighty per cent. As a result, many women elect to have surgery as a risk-reducing strategy. However, the majority of these women do not have any evidence of cancer and surgically induced menopause increases their risk of other diseases, including osteoporosis and cardiovascular disease. A method to determine the need for surgery in this group of ‘at risk’ women is required.
We are trialling a new diagnostic test for the detection of early-stage ovarian cancers in women carrying hereditary mutations in the BRCA1 or BRCA2 genes. Unlike genetic testing, which indicates only a predisposition to develop cancer, this new test identifies biological changes associated with the early stages of cancer formation. By using this test to detect early-stage cancers, the majority of women could be spared the risks of surgery and its associated side-effects.
Our goal is to establish this test in a regular screening program. Successful implementation will greatly decrease the number of women undergoing surgical intervention, allowing the majority to lead full, healthy lives.
Ovarian Cancer Biomarkers
Monash Medical Centre, Melbourne
Royal Adelaide Hospital, Adelaide
The Ovarian Cancer Research Foundation
3. microRNAs – the secret weapon in BRCA1 detection
Global efforts are currently carried out through initiatives such as the Human Variome Project to increase the power of the correlations between rare BRCA mutations and cancer occurrence – but these approaches are mainly based on the more common BRCA1 or BRCA2 mutations.
microRNAs are small regulators of gene expression that play critical roles in multiple diseases including cancer and are secreted in most biofluids such as blood serum, urine and saliva. Our laboratory has discovered that molecular variations exist within microRNAs, which when analysed markedly increase their accuracy in disease prognosis.
BRCA1 directly controls the levels of select microRNAs. As such, microRNA levels can be used to identify mutations, severely impacting the function of BRCA1, even when extremely rare.
In the current project, we are analysing the impact of BRCA1 mutations on molecular variations of these microRNAs in breast cancer samples from The Cancer Genome Atlas, with the aim of defining novel biomarkers linking uncharacterised BRCA1 mutations with breast cancer development and progression.
Nucleic Acids and Innate Immunity
Sanger Institute, UK
University of South Australia, Adelaide
ARC (Future Fellowship)