Oral Presentation Joint 2016 COSA and ANZBCTG Annual Scientific Meeting

RANK Ligand as a Target for Breast Cancer Prevention in BRCA1 Mutation Carriers (#109)

E Nolan 1 2 , F Vaillant 1 2 , D Branstetter 3 , B Pal 1 2 , G Giner 1 2 , L Whitehead 1 , SW Lok 1 4 , GB Mann 2 4 5 6 , k ConFab 7 , K Rohrbach 3 , LY Huang 3 , R Soriano 3 , GK Smyth 1 2 , WC Dougall 3 8 , JE Visvader 1 2 , Geoffrey Lindeman 1 2 4 6
  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  2. The University of Melbourne, Melbourne, VIC, Australia
  3. Amgen Inc, California, United States
  4. The Royal Melbourne Hospital, Melbourne, VIC, Australia
  5. The Royal Women's Hospital, Parkville, VIC, Australia
  6. The Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia
  7. kConFab Consortium, Australia
  8. QIMR Berghofer Medical Research Institute, Brisbane, QLD, 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.

Methods:  Freshly isolated, histologically normal patient specimens from BRCA1 mutation carriers were studied using a variety of assays. RANK expression was evaluated in formalin fixed paraffin embedded archival sections from the kConFab and the Amgen Tissue Banks with HREC approval. The MMTV-cre/Brca1fl/fl/p53+/– mouse model was used to investigate RANKL inhibition as a chemoprevention strategy.

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 in 3D breast organoids derived from pre-neoplastic BRCA1mut/+ tissue attenuated progesterone-induced proliferation. Furthermore, 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 (p<0.001).

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.