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Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue

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An Erratum to this article was published on 08 March 2016

Abstract

Glucocorticoids (GCs) regulate cell homeostasis and can affect carcinogenesis. An inherited germline mutation in the BRCA1 gene, a tumor suppressor gene, confers a predisposition to breast and ovarian cancers. BRCA1 participates in the maintenance of genome stability through DNA repair, in cellular homeostasis through gene transcription, and in signaling regulation. The interaction between BRCA1 and the glucocorticoid receptor (GR) signaling pathway was studied in normal breast tissues and triple-negative breast cancers from BRCA1 mutation carriers. A loss of the active Ser211 phosphorylated form of GR was found in the mutant as compared to the non-mutant. In in vitro studies, the BRCA1 status in breast cancer cell lines regulates GC-dependent proliferation/apoptosis and impacts GC-dependent gene expression. The lack of BRCA1 inhibited dexamethasone actions on its target genes’ expression and the opposite effect was seen with BRCA1 overexpression. BRCA1 overexpression enhances MAPK p38 phosphorylation, resulting in an amplification of GR phosphorylation on Ser 211 and GR basal expression. Our results indicate that BRCA1 is essential to develop an efficient GC signalization. GR P-Ser211 levels may constitute an important diagnostic factor for screening BRCA1 loss of expression in tumors from BRCA1 mutation carriers as well as in sporadic BRCAness tumors. This marker may help to optimize therapeutic strategies.

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Acknowledgments

This research was supported by grants from INSERM-UPMC, HRA Pharma, Paris, and the Institut National du Cancer (INCa, France). Laudine Communal was the recipient of a CIFRE grant from HRA Pharma and the government. Myriam Vilasco was the recipient of a post-doc fellowship (INCa). We are very grateful to Sylvie Dumont and Aurélie Scriva for their technical assistance in immunohistochemistry. We thank Steve K. Nordeen (University of Colorado, Denver, USA) for sequences of IEX-1 primers and Wayne V. Vedeckis (University of Louisiana Health Sciences Center, New Orleans, USA) for providing the hGR 1A and 1B promoter constructs. We also thank Dr Alexandre A. Zukiwski, Dr Philippe le Rouzic, and Neil Insdorf for their kind help in editing the manuscript.

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Authors and Affiliations

  1. INSERM-UPMC Université Paris 06, UMRS 938, Hôpital Saint-Antoine, 75012, Paris, France

    Myriam Vilasco, Laudine Communal, Justine Hugon-Rodin, Zherui Wu, Patricia Forgez & Anne Gompel

  2. Service d’Anatomie et Cytologie Pathologiques, Centre Jean-Perrin, Clermont Ferrand, France

    Frédérique Penault-Llorca

  3. Service d’Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Saint-Antoine, 75012, Paris, France

    Najat Mourra

  4. Unité de Gynécologie Endocrinienne, Université Paris Descartes, AP-HP, Cochin Port Royal, 53, Avenue de l’Observatoire, 75014, Paris, France

    Justine Hugon-Rodin & Anne Gompel

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  1. Myriam Vilasco
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  2. Laudine Communal
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BRACAPS

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Correspondence to Patricia Forgez or Anne Gompel.

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The members of BRACAPS are listed in the Appendix.

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Appendix

Appendix

The members of BRACAPS are as follows: Jean Feunteun, Université Paris XI, Institut Gustave-Roussy; Suzette Delaloge, Institut Gustave-Roussy; Pascal Pujol, INSERM 824, CHU Arnaud de Villeneuve, Montpellier; Marie-Pierre Chauvet, Centre Oscar Lambret, Lille; Murielle Perrault de Jotemps, Clinique Hartmann, Neuilly; and Marc Chaouat, Hopital Saint Louis, Paris.

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Vilasco, M., Communal, L., Hugon-Rodin, J. et al. Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue. Breast Cancer Res Treat 142, 283–296 (2013). https://doi.org/10.1007/s10549-013-2722-8

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