Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence.

More than 70% of human breast cancers (BCs) are estrogen receptor α-positive (ER). A clinical challenge of ER BC is that they can recur decades after initial treatments. Mechanisms governing latent disease remain elusive due to lack of adequate in vivo models. We compare intraductal xenografts of ER and triple-negative (TN) BC cells and demonstrate that disseminated TNBC cells proliferate similarly as TNBC cells at the primary site whereas disseminated ER BC cells proliferate slower, they decrease CDH1 and increase ZEB1,2 expressions, and exhibit characteristics of epithelial-mesenchymal plasticity (EMP) and dormancy. Forced E-cadherin expression overcomes ER BC dormancy. Cytokine signalings are enriched in more active versus inactive disseminated tumour cells, suggesting microenvironmental triggers for awakening. We conclude that intraductal xenografts model ER + BC dormancy and reveal that EMP is essential for the generation of a dormant cell state and that targeting exit from EMP has therapeutic potential.