Breast tumor aromatase: functional role and transcriptional regulation.

Abstract

Aromatase has been shown to be expressed at a higher level in human breast cancer tissue than in normal breast tissue, by means of enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture including MCF-7 breast cancer cells, animal experiments using aromatasetransfected breast cancer cells, and transgenic mouse studies have demonstrated that estrogen production in situ plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase is believed to be able to stimulate breast cancer growth through both autocrine and paracrine pathways, as demonstrated by a three-dimensional cell culture study. RT-PCR and gene transcriptional studies have revealed that the aromatase promoter is switched from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancerous tissue. Recently, we identified and characterized a cAMP-responsive element (CREaro) upstream from promoter I.3 by DNA deletion and mutational analyses. Our results from promoter functional analysis also demonstrated an interaction between the CREaro and the silencer element (S1) that was identified previously in our laboratory. In the presence of cAMP, the positive regulatory CREaro can overcome the action of the silencer on the function of promoter I.3. On the basis of results generated from our own and other laboratories, we propose that, in normal breast adipose stromal cells and fibroblasts, aromatase expression is driven by promoter I.4 (glucocorticoid dependent), and that the action of promoters I.3 and II is suppressed by the silencer negative regulatory element. However, in cancer cells and surrounding adipose stromal cells, the cAMP level increases, and aromatase promoters are switched to cAMP-dependent promoters -I.3 and II. Furthermore, we applied the yeast one-hybrid screening method to search for proteins interacting with the silencer element, S1. The major protein identified was ERRα-1; however, SF-1, which is present in the ovary, is not detected in breast cancer tissue. Using a reporter plasmid with the aromatase genomic fragment containing promoter I.3 and S1, in breast cancer SK-BR-3 cells, ERRα-1 was found to have a positive regulatory function. It is believed that the silencer element in the human aromatase gene may function Endocrine-Related Cancer (1999) 6 149-156 differently in different tissues, as a result of distinct expression patterns of transcription factors.

Antinociception Produced by 14,15-Epoxyeicosatrienoic Acid Is Mediated by the Activation of β-Endorphin and Met-Enkephalin in the Rat Ventrolateral Periaqueductal Gray

“…Recent attention has been focused on those metabolites derived via P450-dependent metabolism of arachidonic acid by epoxygenases to EETs. EETs have been shown to produce vasodilation (Xiao et al, 1998;Chen et al, 1999), activate potassium channels (Gebremedhin et al, 1992), produce anti-inflammatory effects (Inceoglu et al, 2006), and stimulate angiogenesis (Pozzi et al, 2005). Additionally, this investigation supports the novel concept that EETs produce analgesia that is Fig.…”

Selective spatial upregulation of intratumoral stromal aromatase in breast cancer patients: evidence for imbalance of local estrogen metabolism

“…However, there is also growing evidence for intrinsic epigenetic differences between tumor-associated and normal stroma; Chen et al have proposed that physiological aromatase expression in breast fibroblasts is driven by the glucocorticoid-dependent promotor I.4, while the action of promotors I.3 and II are suppressed by the silencer negative regulatory element. In cancer cells and surrounding stroma, cAMP levels increase and aromatase promoters are switched to the cAMPdependent promoters I.3 and II (Chen et al 1999). While the same group has also observed an upregulation in aromatase expression in breast cancer cells themselves through non-genomic action of ERa in conjunction with growth factor-mediated pathways in vitro, our finding of unchanged aromatase protein levels in both normal and malignant breast epithelium somewhat question the clinical relevance of their results (Chen et al 2005).…”

Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.

“…Interestingly, under these conditions all three type II inhibitors (aminoglutethimide, letrozole and anastrozole) failed to realize their full inhibitory potential and, at certain concentrations, were associated with enhanced activity. The lack of full inhibition and the enhanced activity is likely to reflect the reversible nature of these inhibitors and the ability of the inhibitors to induce aromatase mRNA/stabilize aromatase protein which has been reported by Harada et al (1999) and Chen et al (1999). In contrast to these effects, the type I inhibitor, formestane, was always associated with decreased aromatase activity; indeed, inclusion in the 18-h preincubation period tended to produce greater effects than were achieved in the 5-h assay.…”