Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Receptor activator of NF-κB (RANK) and its ligand, RANKL, are essential for osteoclastogenesis and modulate osteolytic bone metastasis. The RANKL/RANK system is also fundamental for mammary gland development and plays a potential role in breast carcinogenesis. c-Src, a nonreceptor tyrosine kinase downstream of RANK, is overexpressed in most breast cancers and plays a key role in several transduction pathways. The aim of the study was to examine the expression of these molecules in tissue microarrays constructed from 62 advanced breast cancers and 10 breast cancers controls (no metastasis after follow-up). Significantly higher levels of RANK and lower levels of RANKL were found in triple-negative (ER-/PR-/HER2-) tumors when compared with luminal subtypes, whereas their levels in the HER2 subtype were quantitatively in between. RANK expression was significantly associated with tumor grade/differentiation by multivariate analysis. Despite their high expression in bone, neither molecule in primary tumors seemed to be related to a bone-seeking phenotype. Rather, they were significantly correlated with a brain-metastatic phenotype. RANKL and RANK were significantly associated with survival outcomes. Further, Src expression showed a significantly positive linear relationship with RANK, suggesting a potential mechanism of the RANKL-RANK axis in regulating breast cancer cell differentiation and antiapoptosis. Thus, these molecules may be potential therapeutic targets, especially in triple-negative tumors, for which the only systemic treatment option is cytotoxic chemotherapy.