EphA2 receptor tyrosine kinase (RTK) is highly expressed in
breast tumor cells across multiple molecular subtypes and correlates with poor patient prognosis. In this study, the potential role of EphA2 in this clinically relevant phenomenon is investigated as
metastasis of
breast cancer to bone is a major cause of morbidity and mortality in patients. It was found that the EphA2 function in
breast cancer cells promotes osteoclast activation and the development of osteolytic
bone disease. Blocking EphA2 function molecularly and pharmacologically in
breast tumors reduced the number and size of bone lesions and the degree of osteolytic disease in intratibial and intracardiac mouse models, which correlated with a significant decrease in the number of osteoclasts at the
tumor-bone interface. EphA2 loss of function in
tumor cells impaired osteoclast progenitor differentiation in coculture, which is mediated, at least in part, by reduced expression of
IL-6. EPHA2 transcript levels are enriched in human
breast cancer bone metastatic lesions relative to visceral metastatic sites;
EphA2 protein expression was detected in
breast tumor cells in bone
metastases in patient samples, supporting the clinical relevance of the study's findings. These data provide a strong rationale for the development and application of molecularly targeted
therapies against EphA2 for the treatment of
breast cancer bone metastatic disease. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and
Mineral Research.