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

Patrick Aouad, Yueyun Zhang, Fabio Martino, Céline Stibolt, Simak Ali, Giovanna Ambrosini, Sendurai A. Mani, Kelly Maggs, Hazel M. Quinn, George Sflomos and Cathrin Brisken ()
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Patrick Aouad: ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Yueyun Zhang: ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Fabio Martino: ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Céline Stibolt: ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Simak Ali: Imperial College London, Hammersmith Hospital Campus
Giovanna Ambrosini: ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Sendurai A. Mani: MD Anderson Cancer Center
Kelly Maggs: Laboratory for Topology and Neuroscience, Brain Mind Institute, EPFL
Hazel M. Quinn: ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
George Sflomos: ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Cathrin Brisken: ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32523-6

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