RANKL Blockade May Aid Breast Cancer Prevention in High-Risk Patients

Individuals who harbor germline mutations in the breast-cancer-susceptibility gene BRCA1 have an increased risk of developing breast cancer. The resulting tumors are often hormone receptor–negative basal-like tumors with deregulated progesterone signaling that have a poor prognosis. Patients carrying BRCA1 mutations often undergo prophylactic mastectomy to reduce the risk of breast cancer, and effective preventative therapies are needed. The receptor activator of nuclear factor kappa-B ligand (RANKL) is an important mediator of progesterone signaling in mammary gland development and tumorigenesis, prompting Nolan and colleagues to investigate the role of RANK–RANKL signaling in the initiation of breast tumorigenesis in patients carrying BRCA1 mutations. Breast tissue from normal, BRCA1-mutation, or BRCA2-mutation women revealed that RANK expression was restricted to normal luminal progenitor (LP) cells in wild-type and BRCA1-mutant breast tissue, with a larger fraction of RANK⁺ LP cells in BRCA1-mutant tissue, suggesting that enhanced RANK expression indicates a perturbed LP population in BRCA1-mutation carriers. RANK⁺ LP cells from BRCA1-mutation carriers exhibited increased clonogenic capacity and proliferation compared to RANK⁻ cells and RANK⁺ cells from wild-type BRCA1 tissue. RANK⁺ LP cells exhibited enrichment of genes involved in cell cycle, proliferation, and DNA repair. Further, RANK⁺ progenitor cells from BRCA1-mutant tissue were more susceptible to DNA damage than RANK⁻ progenitor cells. Data from The Cancer Genome Atlas revealed that RANK⁺ LP cells exhibited a basal-like gene signature, whereas RANK⁻ cells were more similar to other subtypes, suggesting that RANK⁺ LP cells might be a target for breast cancer prevention therapy. The RANKL inhibitor, denosumab, blocked progesterone-induced proliferation in BRCA1-mutant organoids. Further, in a pilot window study, three BRCA1-mutation carriers treated with denosumab exhibited reduced breast epithelial cell proliferation. Finally, in BRCA1-deficient mouse models, RANKL inhibition resulted in delayed tumor onset. Altogether, these data imply that RANK signaling promotes tumorigenesis in BRCA1-mutation carriers, and suggest the potential for RANKL targeting in breast cancer prevention.

Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, et al. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 2016 Jun 20 [Epub ahead of print].

• ©2016 American Association for Cancer Research.