Glucocorticoid receptor repression mediated by BRCA1 inactivation in ovarian cancer.

Abstract

BACKGROUND:

BRCA mutations are the main known hereditary factor for ovarian cancer. Notably, emerging evidence indicates that the glucocorticoid receptor (GR) has drawn considerable interest in ovarian cancer development. However, dynamic cross-talk between BRCA1 and GR signaling pathways are poorly understood.

METHODS:

The regulatory effects of BRCA on GR were assessed in 146 serous ovarian cancer patients (28 pairs of BRCA1-mutated or not, 23 pairs of BRCA2-mutated or not, and 22 pairs with hypermethylated BRCA1 promoter or not). BRCA1 promoter methylation was analyzed by bisulfite sequencing using primers flanking the core promoter region. Expression levels of BRCA1 and GR were assessed by immunohistochemistry and real-time PCR. Regression analysis was used to examine the possible relationship between BRCA1 and GR expression levels. The knockdown and overexpression of BRCA1 were achieved using a lentiviral vector in 293 T cells, SKOV3 ovarian cancer cells, and primary non-mutated and BRCA1-mutated ovarian cancer cells.

RESULTS:

GR expression levels were unchanged in non-BRCA1-mutated, non-BRCA2-mutated and BRCA2-mutated ovarian cancer compared to their normal tissues; BRCA1 repression (BRCA1 mutation or BRCA1 promoter hypermethylation) ovarian cancer showed decreased GR levels compared to normal tissue; there was a positive correlation between BRCA1 and GR expression in human ovarian cancer specimens; BRCA1 knockdown was effective at inhibiting GR expression, and overexpression of BRCA1 induces an increase in GR levels in ovarian cancer cells.

CONCLUSIONS:

These results suggest that GR may be a potential target for BRCA1 in ovarian cancer progression.

• Authors: Yuan-Yuan Fang, Da Li, Chen Cao, Chun-Yan Li, Ting-Ting Li
• Journal: BMC cancer (BMC Cancer) Vol. 14 Pg. 188 (Mar 14 2014) ISSN: 1471-2407 [Electronic] England
• PMID: 24629067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human
• Receptors, Glucocorticoid

Topics

• BRCA1 Protein (genetics, metabolism)
• BRCA2 Protein (genetics, metabolism)
• Chromosomes, Human, Pair 17
• DNA Methylation
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Ovarian Neoplasms (metabolism, pathology)
• Promoter Regions, Genetic
• Receptors, Glucocorticoid (genetics, metabolism)
• Tumor Cells, Cultured