Metastasis is the major cause of death from cancer (1); metastasis to the lymph nodes in breast cancer is dangerous, relatively common, and in one study ranged from 10-60% based on molecular subtype (2-4). We predict therapeutic index is intrinsically linked to differential expression which can be comprehensively and blindly determined using whole transcriptome data (5). We pioneered understanding of metastasis to the lymph nodes as an intermediate biological and anatomical counterpart to the CNS metastasis in humans (6-12). Here we utilize whole transcriptome technologies (13, 14) to measure total transcription in the lymph node metastases and primary tumors of humans with breast cancer for discovery and insight into clonal evolution through disease progression. We identify here a therapeutic target based on its differential expression and up-regulation upon metastasis to the lymph nodes in humans with breast cancer, HUWE1, as a candidate therapeutic target for the medical management of lymph node metastasis.