RANKLed by the Complexity of Signaling in Breast Cancer Metastasis to the Brain

Receptor activator of nuclear factor kappa B ligand (RANKL) and receptor activator of nuclear factor kappa B (RANK) are essential for mammary gland development and carcinogenesis; they also drive thermoregulation and modulate inflammatory activation in the brain. RANK was variably expressed in metastatic breast cancer cells but minimally expressed in the adjacent brain parenchyma. This is in contrast to the expression of RANKL, which was minimal in metastatic breast cancer but highly variable in tumoral stroma. A significant negative correlation between RANK in metastatic tumor and RANKL in tumoral stroma was identified. Background: Receptor activator of nuclear factor kappa B (RANK) and its ligand, RANKL, are essential for mammary gland development and play a vital role in breast carcinogenesis. RANKL-RANK signaling also drives thermoregulation and modulates inflammatory activation in the brain. The expression of RANKL in primary breast cancer (BC) has been negatively associated with brain metastases, while significantly higher levels of RANK are seen in BC with brain metastases. We examined the expression of RANK and RANKL in BC metastasis to the brain. Patients and Methods: We examined the expression of RANK and RANKL in 40 cases of BC metastasis to the brain. Results: RANK was variably expressed in BC cells but minimally expressed in the adjacent brain parenchyma. In contrast, the expression of RANKL was minimal in metastatic BC but highly variable in tumoral stroma. RANKL expression in normal brain stroma obtained during autopsy was negligible. Histologic grade and BC subtypes were not significantly associated with RANK expression in metastatic BC. A significant negative correlation between RANK in metastatic BC and RANKL in tumoral stroma was identified (P < .001). Conclusion: RANK expressed by primary BC and RANKL detected in the tumor microenvironment together participate in cancer development, while the same principle may operate at distant sites. Further investigation is necessary to provide additional insight into the role of the RANKL-RANK pathway in BC progression and to investigate the potential efficacy of therapeutic strategies targeting these molecules in BC metastasis to the brain. (C) 2020 Elsevier Inc. All rights reserved.