| Abstract: |
Cytochrome P450 aromatase, encoded by the CYP19 gene, catalyzes estrogen synthesis. In obese postmenopausal women, increased estrogen synthesis in adipose tissue has been linked to hormone-dependent breast carcinogenesis. Hence, it is important to elucidate the mechanisms that regulate CYP19 gene expression. Prostaglandin E2 (PGE2) stimulates the cyclic AMP (cAMP) → protein kinase A (PKA) → cAMP responsive element binding protein (CREB) pathway leading to increased CYP19 transcription. The prostaglandin transporter (PGT) removes PGE2 from the extracellular milieu and delivers it to the cytosol, where it is inactivated. The main objective of this study was to determine whether PGT regulates CYP19 transcription. Silencing of PGT in preadipocytes increased PGE2 levels in the extracellular medium, thereby stimulating the cAMP → PKA pathway resulting in enhanced interaction between pCREB, p300, and the CYP19 I.3/II promoter. A reciprocal decrease in the interaction between the CYP19 I.3/II promoter and BRCA1, a repressor of CYP19 transcription, was observed. Overexpressing PGT reduced extracellular PGE2 levels, suppressed the cAMP → PKA pathway, enhanced the interaction between BRCA1 and p300, and inhibited aromatase expression. We also compared the PGT → aromatase axis in preadipocytes versus adipocytes. Aromatase levels were markedly increased in preadipocytes versus adipocytes. This increase in aromatase was explained, at least in part, by reduced PGT levels leading to enhanced PGE2 → cAMP → PKA signaling. In addition to regulating aromatase expression, PGT-mediated changes in extracellular PGE2 levels were a determinant of adipocyte differentiation. Collectively, these results suggest that PGT modulates adipogenesis and thereby PGE2-mediated activation of the cAMP → PKA → CREB pathway leading to altered CYP19 transcription and aromatase activity. ©2011 AACR. |
