Aromatase expression is increased in BRCA1 mutation carriers.
BACKGROUND
Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Chand
Ashwini L
AL
Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia. ashwini.chand@princehenrys.org.
Simpson
Evan R
ER
Clyne
Colin D
CD
D017667:Adipocytes / Q000378:metabolism; D000328:Adult; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D001315:Australia; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001940:Breast / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010053:Ovary / Q000378:metabolism
D019313:BRCA1 Protein; D001141:Aromatase