Cancer Cell International
Background: Absence of the estrogen receptor-α (ER) is perhaps the most distinctive pathological feature of breast cancers arising in women who inherit a mutation in BRCA1. Two hypotheses, not necessarily mutually exclusive, exist in the literature that describe mechanisms of ER transcriptional repression in breast cancer. One hypothesis suggests that methylation of cytosine–guanine dinucleotides (CpGs) primarily mediates repression, while the other maintains that transcriptional control is mediated by certain positive and negative promoter elements.
Methods: To determine if wild type BRCA1 could induce activity of the ER promoter, we performed a series of tran- sient transfections with ER promoter segments linked to a luciferase reporter. The effect of BRCA1 on endogenous ER expression was evaluated by RNA analysis.
Results: Following cotransfection with a BRCA1 expression plasmid, we observed that ER promoter-driven luciferase activity was significantly increased in both MCF10A and IMEC cells (p < 0.005 and 0.0005 respectively, two-tailed t test). Specifically, the full length ER promoter construct showed approximately 5.6-fold (MCF10A) and tenfold (IMEC) increases in luciferase activity following BRCA1 transfection, compared with transfection with an empty expression plasmid (i.e. lacking BRCA1 sequence). We localized the ER promoter segment responsible for transactivation by BRCA1 to a 109 bp region containing an AP2γ homologous site.
Conclusions: The work described here, along with previously published work, indicates that activity of certain tran- scriptional regulatory elements and CpG methylation both represent important mechanisms by which the ER gene is typically inactive in breast cancers associated with BRCA1 mutations. The absence of ER in these breast cancers has significant implications for pathogenesis, prevention, and treatment.
Dartmouth Digital Commons Citation
Archey, William B. and Arrick, Bradley A., "Transactivation of the Estrogen Receptor Promoter by BRCA1" (2017). Open Dartmouth: Published works by Dartmouth faculty. 680.