Oral Presentation Victorian Comprehensive Cancer Centre Inaugural Research Conference 2017

RANK ligand as a target for breast cancer prevention in BRCA1 mutation carriers (#76)

Geoffrey Lindeman 1 2 3
  1. Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Familial Cancer Centre, The Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia
  3. Department of Medicine, University of Melbourne, Parkville, VIC, Australia

Background: BRCA1 mutation carriers commonly undergo prophylactic mastectomy to reduce their risk of breast cancer. The identification of an effective and acceptable prevention therapy remains a ‘holy grail’ for the field. Precancerous BRCA1mut/+ tissue contains an aberrant population of progenitor cells and deregulated progesterone signalling has been implicated in BRCA1-associated oncogenesis. Since Receptor Activator of Nuclear Factor-kappa B ligand (RANKL) is a key paracrine effector of progesterone signalling, and RANKL and its receptor RANK contribute to mammary tumorigenesis, we investigated a role for this pathway in preneoplastic breast tissue from BRCA1 mutation carriers and using the MMTV-cre/Brca1fl/fl/p53+/– mouse model, which develops tumours that recapitulate the hallmark features of BRCA1-associated breast cancer.

Results: We identified two subsets of luminal progenitors (RANK+ and RANK–) in histologically normal tissue of BRCA1 mutation carriers. RANK+ cells were highly proliferative, exhibited grossly aberrant DNA repair and bore a molecular signature similar to that of basal-like breast cancer. Moreover, high levels of RANK expression prevailed in established BRCA1-associated tumours. These data suggest that RANK+ and not RANK– progenitors are a key target population in these women. Notably, inhibition of RANKL signalling by denosumab tissue attenuated progesterone-induced proliferation in 3D breast organoids derived from pre-neoplastic BRCA1mut/+. This finding was confirmed in vivo in female BRCA1 mutation carriers treated with denosumab. Notably, inhibition of RANKL with either the RANKL inhibitor OPG-Fc or a RANKL monoclonal antibody in a Brca1-deficient mouse model significantly curtailed mammary tumorigenesis, when compared to controls (Hazard Ratio (logrank) for mammary tumour incidence: 0.23 (95% CI 0.07-0.76).

Conclusions: Together these findings identify a targetable pathway in a putative cell of origin population in BRCA1 mutation carriers and implicate RANKL blockade as a promising breast cancer prevention strategy. An international randomised phase 3 study evaluating denosumab for the Prevention of breast cancer in BRCA1 mutation carriers (‘BRCA-P’) is currently under development to test this hypothesis.