title: Epigenetic mechanisms regulating CYP19 transcription in human breast adipose fibroblasts.
abstract: Cytochrome aromatase p450, encoded by the gene CYP19, catalyzes the synthesis of estrogens from androgens. In post-menopausal women, adipose becomes the major site for estrogen production, where basal CYP19 transcription is driven by distal promoter I.4. In breast adipose fibroblasts (BAFs), CYP19 expression is elevated in the presence of tumour-derived factors through use of promoters I.3 and II. We show for the first time that DNA methylation contributes to CYP19 regulation in BAFs and breast cell lines. Promoter I.4 and I.3/II-derived mRNA were not dependent on the CpG methylation status within respective promoters. However, inhibition of DNA methylation with 5-aza-2'-deoxycytidine resulted in a significant approximately 40-fold induction in CYP19 mRNA expression in BAFs and breast cell lines. These studies uncover a new layer of complexity in the regulation of aromatase where CYP19 appears to be inhibited by DNA methylation and evokes the possibility that disruption to this epigenetic regulation may give rise to an increase in aromatase levels in the breast.
authors.affiliation: Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia. kevin.knower@princehenrys.org
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Knower
authors.forename: Sarah Q
authors.initials: SQ
authors.lastname: To
authors.forename: Evan R
authors.initials: ER
authors.lastname: Simpson
authors.forename: Colin D
authors.initials: CD
authors.lastname: Clyne
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000502:physiology; D015257:DNA-Cytosine Methylases / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D001141:Aromatase; C081573:DNA modification methylase SssI; D015257:DNA-Cytosine Methylases