title: Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue.
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.
authors.affiliation: INSERM-UPMC Université Paris 06, UMRS 938, Hôpital Saint-Antoine, 75012, Paris, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Vilasco
authors.forename: Laudine
authors.initials: L
authors.lastname: Communal
authors.forename: Justine
authors.initials: J
authors.lastname: Hugon-Rodin
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: Najat
authors.initials: N
authors.lastname: Mourra
authors.forename: Zherui
authors.initials: Z
authors.lastname: Wu
authors.forename: Patricia
authors.initials: P
authors.lastname: Forgez
authors.forename: Anne
authors.initials: A
authors.lastname: Gompel
mesh_terms: D000328:Adult; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D012694:Serine
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D012694:Serine; D003907:Dexamethasone