We demonstrate that sustained expression of both Ephrin-A3 and novel EFNA3 lncRNAs increased the metastatic potential of human breast cancer cells, possibly by increasing the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. In agreement, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients. hypoxia could contribute to metastatic spread of breast cancer via HIF-mediated induction ofEFNA3lncRNAs and subsequent Ephrin-A3 protein accumulation.