Abstract P3-11-05: RANK ligand is a target for breast cancer prevention in BRCA1 mutation carriers
Authors: Lindeman GJ , Nolan E , Pal B , Vaillant F , Giner G , Whitehead L , Mann GB , Lok SW , Shackleton K ,   Kathleen Cuningham Foundation Consortium (kConFab), Smyth GK , Visvader JE 
Published: May 2016

Background: BRCA1 mutation carriers often undergo prophylactic mastectomy to minimize their risk of breast cancer. The value of targeting ovarian hormones to prevent breast tumorigenesis remains contentious and the identification of an effective and acceptable chemoprevention strategy remains a 'holy grail' for the field. Recently, luminal progenitor cells have been identified as the likely cell-of-origin for BRCA1-associated breast tumors1. In addition, deregulated progesterone signaling has been implicated as a potential mechanism underlying tumor development in Brca1-deficient mammary glands2, although its role in luminal progenitor activation in BRCA1 mutation carriers is unknown. RANKL (Receptor Activator of Nuclear Factor-kappa B Ligand) has been identified as a key paracrine effector of progesterone-induced mammary epithelial proliferation in both mouse and human tissue3-5. Notably, RANKL and its receptor RANK play a critical role in the development of breast cancer, with inhibition of RANKL resulting in attenuation of tumorigenesis in mouse models of hormone-driven mammary carcinogenesis6,7.

Methods: We explored a role for the RANK/RANKL pathway during the preneoplastic phase in freshly isolated, histologically normal specimens from BRCA1 mutation carriers using a combination of strategies. RANK and RANKL expression in breast cancer was also evaluated in formalin fixed paraffin embedded (FFPE) archival sections by IHC. All samples were obtained with relevant IRB approval. A role for RANKL inhibition in attenuating tumor onset was studied using models that recapitulate human basal-like cancer.

Results: A RANK+ subset of luminal progenitor cells was identified in histologically normal breast tissue from BRCA1-mutation carriers. The RANK+ luminal progenitors exhibited higher proliferative activity compared to RANK- progenitors. RNA profiling revealed a distinctive molecular signature, consistent with the RANK+ subset being a possible target for neoplastic transformation. In established BRCA1-associated breast tumors, a four-fold higher incidence of RANK expression was observed, compared to tumors from non-carriers. In ongoing work, histologically normal pre-neoplastic BRCA1mut/+ tissue is being studied using ex vivo breast organoid assays to determine whether RANKL inhibition can attenuate breast epithelial proliferation.

Conclusions: Our data raise the possibility that RANK signaling is implicated in the initiation of tumorigenesis in BRCA1 mutation carriers (and possibly other high risk women) and that RANKL is a promising chemoprevention target. The findings are of sufficient interest to have led to a clinical trial, BRCA-D (Registered as ACTRN12614000694617). A finalized abstract will be submitted in early September, during the Late-Breaking Abstract submission period.

References:

1. Lim et al Nature Med 2009: 15, 907-13.

2. Poole et al Science 2006: 314, 1467-70.

3. Asselin-Labat et al Nature 2010: 465, 798-802.

4. Joshi et al Nature 2010: 465, 803-7.

5. Tanos et al Sci Transl Med 2013: 5, 182ra55.

6. Schramek et al Nature 2010: 468, 98-102.

7. Gonzales-Suarez et al Nature 2010: 468, 103-7.

Citation Format: Lindeman GJ, Nolan E, Pal B, Vaillant F, Giner G, Whitehead L, Mann GB, Lok SW, Shackleton K, Kathleen Cuningham Foundation Consortium (kConFab), Smyth GK, Visvader JE. RANK ligand is a target for breast cancer prevention in BRCA1 mutation carriers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-11-05.