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Nuclear translocation of MRTFA in MCF7 breast cancer cells shifts ERα nuclear/genomic to extra-nuclear/non genomic actions.
Jehanno, Charly; Percevault, Frédéric; Boujrad, Noureddine; Le Goff, Pascale; Fontaine, Coralie; Arnal, Jean-François; Primig, Michael; Pakdel, Farzad; Michel, Denis; Métivier, Raphaël; Flouriot, Gilles.
Affiliation
  • Jehanno C; Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France; University Hospital Basel, University of Basel, Basel, Switzerland.
  • Percevault F; Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France.
  • Boujrad N; Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France.
  • Le Goff P; Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France.
  • Fontaine C; INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
  • Arnal JF; INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
  • Primig M; Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France.
  • Pakdel F; Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France.
  • Michel D; Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France.
  • Métivier R; Univ Rennes, Institut de Génétique et Développement de Rennes, UMR 6290 CNRS, Rennes, France.
  • Flouriot G; Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France. Electronic address: gilles.flouriot@univ-rennes1.fr.
Mol Cell Endocrinol ; 530: 111282, 2021 06 15.
Article in En | MEDLINE | ID: mdl-33894309
ABSTRACT
The Myocardin-related transcription factor A [MRTFA, also known as Megakaryoblastic Leukemia 1 (MKL1))] is a major actor in the epithelial to mesenchymal transition (EMT). We have previously shown that activation and nuclear accumulation of MRTFA mediate endocrine resistance of estrogen receptor alpha (ERα) positive breast cancers by initiating a partial transition from luminal to basal-like phenotype and impairing ERα cistrome and transcriptome. In the present study, we deepen our understanding of the mechanism by monitoring functional changes in the receptor's activity. We demonstrate that MRTFA nuclear accumulation down-regulates the expression of the unliganded (Apo-)ERα and causes a redistribution of the protein localization from its normal nuclear place to the entire cell volume. This phenomenon is accompanied by a shift in Apo-ERα monomer/dimer ratio towards the monomeric state, leading to significant functional consequences on ERα activities. In particular, the association of Apo-ERα with chromatin is drastically decreased, and the remaining ERα binding sites are substantially less enriched in ERE motifs than in control conditions. Monitored by proximity Ligation Assay, ERα interactions with P160 family coactivators are partly impacted when MRTFA accumulates in the nucleus, and those with SMRT and NCOR1 corepressors are abolished. Finally, ERα interactions with kinases such as c-src and PI3K are increased, thereby enhancing MAP Kinase and AKT activities. In conclusion, the activation and nuclear accumulation of MRTFA in ERα positive breast cancer cells remodels both ERα location and functions by shifting its activity from nuclear genome regulation to extra-nuclear non-genomic signaling.
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Full text: 1 Database: MEDLINE Main subject: Breast Neoplasms / Trans-Activators / Cell Nucleus / Estrogen Receptor alpha Limits: Female / Humans Language: En Year: 2021 Type: Article

Full text: 1 Database: MEDLINE Main subject: Breast Neoplasms / Trans-Activators / Cell Nucleus / Estrogen Receptor alpha Limits: Female / Humans Language: En Year: 2021 Type: Article