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Slug/Pcad pathway controls epithelial cell dynamics in mammary gland and breast carcinoma

Oncogene volume 37, pages 578–588 (2018)Cite this article

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Abstract

Mammary gland morphogenesis results from the coordination of proliferation, cohort migration, apoptosis and stem/progenitor cell dynamics. We showed earlier that the transcription repressor Slug is involved in these functions during mammary tubulogenesis. Slug is expressed by a subpopulation of basal epithelial cells, co-expressed with P-cadherin (Pcad). Slug-knockout mammary glands showed excessive branching, similarly to Pcad-knockout. Here, we found that Slug unexpectedly binds and activates Pcad promoter through E-boxes, inducing Pcad expression. We determined that Pcad can mediate several functions of Slug: Pcad promoted clonal mammosphere growth, basal epithelial differentiation, cell–cell dissociation and cell migration, rescuing Slug depletion. Pcad also promoted cell migration in isolated cells, in association with Src activation, focal adhesion reorganization and cell polarization. Pcad, similarly to Slug, was required for in vitro 3D tubulogenesis. Therefore, Pcad appears to be responsible for epithelial–mesenchymal transition-linked plasticity in mammary epithelial cells. In addition, we found that genes from the Slug/Pcad pathway components were co-expressed and specifically correlated in human breast carcinomas subtypes, carrying pathophysiological significance.

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Abbreviations

ChIP:

Chromatin immunoprecipitation

CK5:

Cytokeratin 5

CK8:

Cytokeratin 8

EMT:

Epithelial–mesenchymal transition

Ecad:

E-cadherin

ESR1:

Estrogen receptor 1

H2:

HER2

KO:

Knocked-out

Lum A:

Luminal A

Lum B:

Luminal B

Ncad:

N-cadherin

Nl:

Normal-like

Pcad:

P-cadherin

RFS:

Recurrence-free survival

SMA:

Smooth muscle actin.

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Acknowledgements

Financial support was provided by the Fondation de France (no. E 2009 006685), the Ligue Nationale contre le Cancer, the Ligue Régionale contre le Cancer (Languedoc-Roussillon and Ardèche) and Aide à la Recherche en Partenariat avec Entreprises (ARPE-Languedoc-Roussillon). In addition, the authors gratefully acknowledge support from the Ligue Régionale (Ardèche) and Nationale contre le Cancer for Y Idoux-Gillet and Association pour la Recherche sur le Cancer for M Nassour. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to L Larue for plasmid vector Ecad, Professor M Takeichi for Pcad vector, Marisa M Faraldo and Marie-Ange Deugnier for Luciferase gene reporter and constructive discussions.

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  1. Y Idoux-Gillet, M Nassour and E Lakis: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France

    Y Idoux-Gillet, M Nassour, E Lakis, F Bonini, C Theillet, S Du Manoir & P Savagner

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  1. Y Idoux-Gillet
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Correspondence to P Savagner.

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Idoux-Gillet, Y., Nassour, M., Lakis, E. et al. Slug/Pcad pathway controls epithelial cell dynamics in mammary gland and breast carcinoma. Oncogene 37, 578–588 (2018). https://doi.org/10.1038/onc.2017.355

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