Effect of BRCA1 on epidermal growth factor receptor in ovarian cancer

Abstract

BackgroundBoth BRCA1 and epidermal growth factor receptor (EGFR) play a critical role in ovarian cancer progression. However, the crosstalk between BRCA1 and EGFR signaling pathways in ovarian cancer remains largely unknown.MethodsThe effect of BRCA1 on EGFR was 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 EGFR were assessed by immunohistochemistry and real-time PCR. 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.ResultsEGFR expression was increased in all cancer tissues compared to normal tissues. Additionally, EGFR expression was higher in normal tissues of BRCA1-mutated patients, and was further increased in cancer tissues; EGFR levels were also significantly elevated in ovarian cancer with promoter hypermethylation-mediated inactivation of BRCA1. BRCA1 knockdown was an effective way to activate EGFR expression in ovarian cancer cells.ConclusionsThese results indicate that BRCA1 may be a potential trigger in transcriptional regulation of EGFR in the development of ovarian cancer.

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

“…4 Recent research has confirmed that BRCA1 is an important transcriptional regulator, and BRCA1 -depleted breast cancer cells shows changes to approximately 7% of the mRNAs expressed [4]. Moreover, our recent study also indicated that angiotensin II type 1 receptor and epidermal growth factor receptor displayed different expression patterns in BRCA1 -defective cancer cells [5,6], and confirmed that differential epigenetic regulation of transcription exist along with BRCA1 inactivation [7,8]. Therefore, one can speculate that there are wide ranges of gene expression and regulation differences between BRCA1 dysfunction and the basal phenotype.…”

Perspectives on Epidermal Growth Factor Receptor Regulation in Triple-Negative Breast Cancer

“…The high incidence of EGFR overexpression in TNBC suggests that the probability that BRCA1 mutant breast cancers harbor EGFR overexpression is high. Recent evidence from both ovarian and breast cancer research shows that BRCA1 loss in human breast and ovarian cancer samples and BRCA1-deficient breast cancer models leads to upregulation of EGFR (Burga et al, 2011;Li et al, 2013;van Diest, van der Groep, & van der Wall, 2006), suggesting that the activity of these signaling molecules are linked, presenting opportunity for targeting EGFR in BRCA1-deficient patients. Experimental modeling using Brca1-deficient mice confirms this notion as targeting EGFR was effective in increasing the time of disease-free survival of the Brca1-deficient animals treated with erlotinib compared to placebo (Burga et al, 2011).…”

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

“…The epidermal growth factor (EGF) receptor (EGFR) is upregulated in ovarian cancer, and increased expression is associated with reduced survival rate [12][13][14][15]. EGFR is emerging as an important therapeutic target for several epithelial tumors, including ovarian cancer.…”