Project Funding Details

Women with a BRCA1 mutation have a high lifetime risk of developing breast (and ovarian) cancer, often at an early age. Regular screening can detect cancers at an early stage, but does not prevent the cancer itself. Most women do not opt for risk-reducing preventive (‘prophylactic’) mastectomy. For this reason a suitable prevention therapy that is both safe and effective remains a ‘holy grail’. Apart from mastectomy, prevention strategies available to BRCA1 mutation carriers include the antioestrogen tamoxifen and/or removal of the ovaries (the latter primarily to reduce ovarian cancer risk). There is good evidence that tamoxifen reduces the incidence of oestrogen receptor (ER) positive tumours in high-risk women, but its role in BRCA1 mutation carriers is unresolved. Moreover, there has been poor uptake of tamoxifen in the clinic, even when prescribed by clinicians. Our group recently identified a protein, called RANKL, as a potential target for breast cancer prevention for BRCA1 mutation carriers (and possibly other high-risk women). The drug denosumab is a RANKL inhibitor currently used to treat osteoporosis or breast cancer spread to bone. Our findings suggest that it could be ‘repurposed’ as a prevention agent. In this study we will compare the relative effectiveness of tamoxifen, removal of the ovaries and RANKL inhibition in pre-clinical BRCA1 models, and also determine whether RANKL has any relevance to BRCA1-associated ovarian cancer. These findings will provide a basis for optimising a clinical trial protocol aimed at preventing breast cancer in women at high genetic risk for developing breast cancer.