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Cyclin A2, a novel regulator of EMT

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Abstract

Our previous work showed that Cyclin A2 deficiency promotes cell invasion in fibroblasts. Given that the majority of cancers emerge from epithelia, we explored novel functions for Cyclin A2 by depleting it in normal mammary epithelial cells. This caused an epithelial to mesenchymal transition (EMT) associated with loss of cell-to-cell contacts, decreased E-Cadherin expression and increased invasive properties characterized by a reciprocal regulation of RhoA and RhoC activities, where RhoA-decreased activity drove cell invasiveness and E-Cadherin delocalization, and RhoC-increased activity only supported cell motility. Phenotypes induced by Cyclin A2 deficiency were exacerbated upon oncogenic activated-Ras expression, which led to an increased expression of EMT-related transcriptional factors. Moreover, Cyclin A2-depleted cells exhibited stem cell-like properties and increased invasion in an in vivo avian embryo model. Our work supports a model where Cyclin A2 downregulation facilitates cancer cell EMT and metastatic dissemination.

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Abbreviations

CycA2:

Cyclin A2

EMT:

Epithelial to mesenchymal transition

NMuMG:

Normal murine mammary gland

TGFβ:

Transforming growth factor β

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Acknowledgments

This work was supported by a grant from the Association pour la Recherche contre le Cancer (ARC). N.B. was supported by fellowships from the French Ministry of Education and Research and the Fondation pour la Recherche Médicale (FRM). C.C. was supported by fellowships from the Canadian Institutes of Health Research and La Ligue Contre le Cancer. The authors declare no competing financial interests. This work was made possible thanks to the MRI imaging facility. We are grateful to Robert Hipskind, Gilles Gadéa and Pierre Roux for their helpful discussions and comments on our manuscript.

Conflict of interest

The authors disclose no potential conflicts of interest.

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Authors and Affiliations

  1. Institut de Génétique Moléculaire de Montpellier, CNRS, 1919 route de Mende, 34293, Montpellier, France

    Nawal Bendris, Caroline T. Cheung, Jean Marie Blanchard & Bénédicte Lemmers

  2. Université Montpellier 2, Place Eugène Bataillon, 34095, Montpellier, France

    Nawal Bendris, Caroline T. Cheung, Jean Marie Blanchard & Bénédicte Lemmers

  3. Université Montpellier 1, 5 Bd Henry IV, 34967, Montpellier, France

    Nawal Bendris, Caroline T. Cheung, Jean Marie Blanchard & Bénédicte Lemmers

  4. Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75235, USA

    Nawal Bendris

  5. Translational Prostate Cancer Research Group, London Regional Cancer Program, London, ON, Canada

    Hon Sing Leong, John D. Lewis & Ann F. Chambers

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  1. Nawal Bendris
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  2. Caroline T. Cheung
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  3. Hon Sing Leong
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Correspondence to Bénédicte Lemmers.

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Bendris, N., Cheung, C.T., Leong, H.S. et al. Cyclin A2, a novel regulator of EMT. Cell. Mol. Life Sci. 71, 4881–4894 (2014). https://doi.org/10.1007/s00018-014-1654-8

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