Abstract
Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue-specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7) aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs) are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for specific hormone-dependent breast cancer.
Highlights
Aromatase is a member of the cytochrome P450 enzyme family and a product of the CYP 19A1 gene [1]
Aromatase consists of two components: the hemoprotein aromatase cytochrome P450 encoded by the CYP19A1 gene and expressed only in steroidogenic cells, and the flavoprotein NADPH-cytochrome P450 reductase, expressed ubiquitously in many cell types [2,3,4]
The aromatase gene and tissue-specific promoter expression Human aromatase is a 58 kDa protein which was first purified from placental microsomes in 1980s [9]
Summary
Aromatase is a member of the cytochrome P450 enzyme family and a product of the CYP 19A1 gene [1]. Until now ~ 300 natural products, most of them are phytoestrogens, have been evaluated for their ability to inhibit aromatase using noncellular (mostly using human microsome as a source of aromatase enzyme), cell-based, and in vivo aromatase inhibition assays [61,83,84,85]; only a few studies (biochanin A from red clover, genistein from soybean, quercetin, isoliquiritigenin from licorice, resveratrol from grape peel and extracts of grape seeds, Figure 3) have been reported for their effect on aromatase promoter I.4, I.3/II activity [86,87,88,89,90,91]. In SK-BR-3 cells resveratrol significantly reduced aromatase mRNA and protein expression in a dose-dependent manner [91] This compound was able to repress the transactivation of CYP19 promoters I.3 and II in SK-BR-3 cells [91], which indicate that resveratrol could be able to reduce localized estrogen production in breast cancer cells. Extensive investigations in natural products seem promising or necessary
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