Perrotta, R. M.; Berton, M.; Valencia Salazar, L.; Mahmoud, Y.; Perez Saez, J. M.; Dalotto-Moreno, T.; Morales, R. M.; Gatto, S. G.; Aguirre-Ghiso, J. A.; Rabinovich, G. A.; Salatino, M.

Early dissemination of breast cancer cells can occur before clinically detectable tumor progression; yet the molecular programs enabling this process remain poorly defined. Here, we identify a conserved glycocheckpoint, mediated by the galectin-1 (GAL1)-glycan axis, that links normal mammary gland morphogenesis to early breast cancer dissemination and metastasis. During mammary gland development, regulated GAL1 expression and glycan accessibility directed epithelial lineage specification and progesterone-induced branching morphogenesis. This morphogenetic program was aberrantly reactivated in early breast cancer lesions and co-opted to promote tumor cell dissemination. Genetic ablation and pharmacological inhibition of GAL1 in mouse models (mammary tumor virus-polyoma middle T antigen (MMTV-PyMT and MMTV-HER2), together with patient-derived data, revealed that this lectin drives epithelial-to-mesenchymal transition, acquisition of stem-like traits, and metastatic competence in breast cancer. Therapeutic targeting of GAL1 reduced early lesions and their progression, decreased circulating tumor cell frequency, and limited lung metastasis in the MMTV-HER2 tumor model. Consistently, high transcriptomic levels of GAL1 together with low levels of the enzyme {beta}-galactoside 2,6-sialyltransferase 1 (ST6GAL1), that catalyzes 2,6-linked sialylation and limits GAL1 binding, was associated with poor clinical outcome in breast cancer patients. These findings reveal that early breast cancer dissemination hijacks a GAL1-glycan morphogenetic program, uncovering a direct link between mammary development and metastatic progression, highlighting GAL1 as a therapeutic vulnerability in early-stage disease.