WEDNESDAY, Nov. 14 (HealthDay News) -- The BRCA1 gene plays a critical role in estrogen receptor (ER) gene expression, which explains why most BRCA1-mutant breast cancers are ER-negative, according to research published in the Nov. 21 issue of the Journal of the National Cancer Institute.
Alison M. Hosey, Ph.D., of Queen's University Belfast in Northern Ireland, and colleagues studied human breast cancer cells to elucidate the molecular basis for the ER-negative phenotype of BRCA1-mutant tumors. The researchers compared gene expression in 17 BRCA1-mutant tumors and 14 sporadic tumors, and used molecular techniques to assess the role of BRCA1 in modulating expression of the estrogen receptor. Response to the anti-estrogen drug fulvestrant was tested in relation to BRCA1 status.
The researchers found that levels of the gene encoding the ER were 5.4-fold lower in BRCA1-mutant tumors compared to sporadic tumors. Transfection of a functional BRCA1 gene into ER-negative, BRCA1-mutant cells restored ER production, whereas knockdown of BRCA1 expression in ER-positive cells halted ER production. Furthermore, the investigators found that BRCA1 binds to the estrogen receptor 1 promoter and acts in concert with the Oct-1 transcription factor to activate ER transcription. Finally, ER-positive cells in which BRCA1 was artificially depleted were resistant to the anti-estrogen fulvestrant, but expression of exogenous ER-alpha restored sensitivity to fulvestrant.
"Our results suggest that BRCA1-mutant tumors fail to express ER-alpha due to the loss of BRCA1-mediated transcriptional activation of [the gene encoding the ER]," the authors conclude.
Abstract
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