Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells.
Adipose tissue provides an important extragonadal source of estrogen. Obesity-associated elevation of estrogen production increases risk of breast cancer in postmenopausal women. Aromatase (CYP19), which converts androgen to estrogen, is a key enzyme in estrogen biosynthesis. In normal adipose tissue, transcription of the aromatase gene is initiated from a relatively weak adipose-specific promoter (I.4). However, in breast cancer, a switch of promoter utilization from I.4 to a strong ovary-specific promoter, PII, leads to increased aromatase expression and, hence, elevated estrogen production. Here, we report an intriguing relationship between the breast cancer susceptibility gene BRCA1 and aromatase expression in human adipose stromal cells (ASCs). Upon stimulation by phorbol ester or dexamethasone, increased aromatase expression in ASCs was accompanied by significant reduction of the BRCA1 level. In addition, adipogenesis-induced aromatase expression was also inversely correlated with BRCA1 abundance. Downregulation of BRCA1 expression in response to various stimuli was through distinct transcription or posttranscription mechanisms. Importantly, siRNA-mediated knockdown of BRCA1 led to specific activation of the breast cancer-associated PII promoter. Therefore, in addition to its well-characterized activities in breast epithelial cells, a role of BRCA1 in modulation of estrogen biosynthesis in ASCs may also contribute to its tissue-specific tumor suppressor function.
Ghosh
Sagar
S
Univ. of Virginia, Charlottesville, VA 22908, USA. rl2t@virginia.edu
Lu
Yunzhe
Y
Katz
Adam
A
Hu
Yanfen
Y
Li
Rong
R
D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009928:Organ Specificity; D010053:Ovary / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation
D019313:BRCA1 Protein; D003907:Dexamethasone; D001141:Aromatase; D013755:Tetradecanoylphorbol Acetate