%0 Journal Article
%T Aromatase expression is increased in BRCA1 mutation carriers
%A Ashwini L Chand
%A kConFab
%A Evan R Simpson
%A Colin D Clyne
%J BMC Cancer
%D 2009
%I BioMed Central
%R 10.1186/1471-2407-9-148
%X We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women.We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts.Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers.The roles of BRCA1 in cellular functions include cell cycle control, protein degradation, DNA damage repair, and transcriptional regulation of its target genes. One of its target genes is aromatase (CYP19A1), the enzyme that catalyses the conversion of C19 steroids into bioactive estrogens [1]. In vitro studies demonstrate the direct binding of BRCA1 to the proximal promoter region of CYP19A1 (promoter II) and as a consequence the repression of transcription [2,3]. Gene silencing of BRCA1 leads to an inability to impair aromatase gene expression and enzyme activity [2-5]. However, whether this leads to aromatase excess in BRCA1 mutation carriers is unknown.This link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in mutation carriers. Given that aromatase is critical in promoting tumour growth and BRCA1 and 2 mutations account for an 80% increased risk in hereditary breast and ovarian cancer development, it is important to investigate the relationship between BRCA1 and aromatase expression in patients.The mechanism with which aromatase exerts its activity in a tissue-specific manner is via transcriptional regulation of multiple promoters on its gene [6].
%U http://www.biomedcentral.com/1471-2407/9/148