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01-11-2013 | Preclinical Study

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

Authors: Myriam Vilasco, Laudine Communal, Justine Hugon-Rodin, Frédérique Penault-Llorca, Najat Mourra, Zherui Wu, Patricia Forgez, Anne Gompel, BRACAPS

Published in: Breast Cancer Research and Treatment | Issue 2/2013

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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Title: Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue
Authors: Myriam Vilasco
Laudine Communal
Justine Hugon-Rodin
Frédérique Penault-Llorca
Najat Mourra
Zherui Wu
Patricia Forgez
Anne Gompel
BRACAPS
Publication date: 01-11-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-013-2722-8

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