SUMMARY Metastasis is responsible for the majority of breast cancer-related deaths, however identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immature THY1 + / VEGFA + tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene, LMO2 . Higher abundance of LMO2 + basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients. Using MMTV-PyMT/Lmo2 CreERT2 mice, we demonstrated that Lmo2 lineage- traced cells have a higher propensity to metastasize. LMO2 knockdown in human breast tumors reduced lung metastasis by impairing intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 binds to STAT3 and is required for STAT3 activation by TNFα and IL6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis. One sentence summary LMO2 modulates STAT3 signaling in breast cancer metastasis.

LMO2 is critical for early metastatic events in breast cancer