Up to 50% of patients with HER2+ subtype breast cancer develop metastasis to the central nervous system, most commonly the brain, demanding rapid therapeutic approaches to limit spread of the HER2+ primary tumor to distant sites (1-3). We recently described the existence of a group of genes that reside proximal to ERBB2 (the gene that encodes the human epidermal growth factor HER2) at 17q12: their differential expression in HER2+ breast cancer, their up-regulation in HER2+ breast cancer, their differential expression and up-regulation in central nervous system (CNS) metastasis and, based on human survival studies, their function in supporting metastasis to the CNS, indicating that the predilection of HER2+ patients to develop CNS metastasis was a phenomena attributable to the disease and not HER2+-targeted therapies (4). Disease recurrence following disease remission (relapse), resistance to trastuzumab or otherwise inadequate long-term control of disease are challenges that limit effectiveness of existing HER2+-targeted therapies. We utilized whole transcriptome technologies (5, 6) to measure total transcription in the primary tumors of humans with HER2+ breast cancer, identifying genes in the HER2 signature based on difference from the luminal A and luminal B tumor transcriptomes. We describe here a candidate therapeutic target up-regulated and differentially expressed in human HER2+ breast cancer, E2F8, as a candidate therapeutic target for the prevention and management of CNS metastasis in HER2+ breast cancer.