Grape Seed Extract Is an Aromatase Inhibitor and a Suppressor of Aromatase Expression

Kijima, Ikuko; Phung, Sheryl; Hur, Gene; Kwok, S.; Chen, Shiuan

doi:10.1158/0008-5472.can-06-0053

Cited by 71 publications

(71 citation statements)

References 54 publications

(47 reference statements)

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“…In particular, CRE and GRE binding sites can regulate aromatase expression in MEC and breast cancer cells (Simpson & Zhao 1996, Young & MacPhaul 1998, Kijima et al 2006. We found that CRE, but not GRE, activity was enhanced in p53-inactivated MEC.…”

Section: H K Choi S H Roh Et Al: Aromatase Overexpresses In P53-inamentioning

confidence: 55%

Enhanced expression of aromatase in p53-inactivated mammary epithelial cells

Choi¹,

Roh²,

Kim³

et al. 2008

Endocrine Related Cancer

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Both the functional loss of p53 and the overexpression of aromatase are important for the progression of breast cancer in postmenopausal women. Here, we found that aromatase expression was up-regulated in primary cultures of mammary epithelial cells (p53 D5,6 MEC) isolated from mice with a defect in exons 5 and 6 of the p53 gene. Aromatase basal activity and expression levels were significantly increased in p53 D5,6 MEC when compared with wild-type MEC. Reporter gene activity in p53 D5,6 MEC transfected with the aromatase promoter or the cAMP-responsive element (CRE) minimal promoter was higher than wild-type MEC. p53 inactivation increased both Ser133-phosphorylated CRE-binding protein (CREB) and the nuclear accumulation of CREB. Inhibition of extracellular signal-regulated kinase (ERK) or Src tyrosine kinase blocked aromatase gene transactivation and CREB activation in the p53 D5,6 MEC. These results support the hypothesis that a genetic defect in the function of p53 enhances the expression of aromatase via ERK or Src activation in MEC, which suggests that aromatase expression is closely related to the p53 status in MEC.

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Section: H K Choi S H Roh Et Al: Aromatase Overexpresses In P53-inamentioning

confidence: 55%

Enhanced expression of aromatase in p53-inactivated mammary epithelial cells

Choi¹,

Roh²,

Kim³

et al. 2008

Endocrine Related Cancer

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“…Cells were transfected with pGL3-Basic-pI.3/II reporter plasmids (À251/+74 or À329/+284 bp) using Lipofectamine 2000 (Invitrogen), as described previously (29). The total amount of DNA (per well) used for cotransfection was 2 Ag.…”

Section: Methodsmentioning

confidence: 99%

“…MCF-7 and H295R cells were transfected with C/EBPy and/or p65 expression plasmids (empty plasmid as a control). After a 24-h incubation after the transfection, cells were lysed and applied for Western blotting using anti-C/EBPy antibody (Santa Cruz Biotechnology) or p65 antibody (Cell Signaling Technology), as described previously (29). The blot was reprobed with anti-actin (Santa Cruz Biotechnology) as a loading control.…”

Section: Methodsmentioning

confidence: 99%

CCAAT/Enhancer Binding Protein δ Up-regulates Aromatase Promoters I.3/II in Breast Cancer Epithelial Cells

Kijima

Glackin

et al. 2008

Cancer Research

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Aromatase is the enzyme responsible for the last step of estrogen synthesis. The female hormone, estrogen, is known to stimulate breast cancer cell growth. Because the expression of aromatase in breast cancer tissues is driven by unique promoters I.3 and II, a more complete understanding of the regulatory mechanism of aromatase expression through promoters I.3/II in breast tumors should be valuable in developing targeted therapies, which selectively suppress estrogen production in breast tumor tissue. Results from in vivo footprinting analyses revealed several protein binding sites, numbered 1 to 5. When site 2 (À124/À112 bp, exon I.3 start site as +1) was mutated, promoters I.3/II activity was dramatically reduced, suggesting that site 2 is a positive regulatory element. Yeast one-hybrid screening revealed that a potential protein binding to site 2 was CCAAT/enhancer binding protein D (C/EBPD). C/EBPD was shown to bind to site 2 of aromatase promoters I.3/II in vitro and in vivo. C/EBPD up-regulated promoters I.3/II activity through this site and, as a result, it also up-regulated aromatase transcription and enzymatic activity. p65, a subunit of nuclear factor-KB (NF-KB) transcription factor, inhibited C/EBPDup-regulated aromatase promoters I.3/II and enzymatic activity. This inhibitory effect of p65 was mediated, in part, through prevention of the C/EBPD binding to site 2. This C/EBPD binding site in aromatase promoters I.3/II seems to act as a positive regulatory element in non-p65-overexpressing breast cancer epithelial cells, whereas it is possibly inactive in p65 overexpressing cancer epithelial cells, such as estrogen receptor-negative breast cancer cells. [Cancer Res 2008; 68(11):4455-64]

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“…Whether cultured breast cancer cell lines express a detectable amount of aromatase is still debatable. While some groups were able to detect aromatase expression in cell lines such as MCF-7, T47D, and MDA-MB-468 (Kijima et al 2006, Miki et al 2007, Ciolino et al 2011), others could not (Sanderson et al 2001, Heneweer et al 2005. Nevertheless, the data that we obtained from KGN cells should be applicable to breast tumor cells as PII-mediated expression is regulated mainly by the cAMP-protein kinase A pathway in both cell types (Zhao et al 1996a, Ghosh et al 2008.…”

Section: Discussionmentioning

confidence: 75%

Methylseleninic acid is a novel suppressor of aromatase expression

Gao

Zhao²,

Liu³

et al. 2011

Journal of Endocrinology

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Elevated circulating estrogen levels, as a result of increased peripheral aromatization of androgens by aromatase, have been indicated to underlie the association between obesity and a higher risk of breast cancer in postmenopausal women. Although aromatase inhibitors have been used as a first-line therapy for estrogen receptor-positive breast cancer in postmenopausal women, their potential as breast cancer chemopreventive agents has been limited due to toxicities and high costs. It is therefore imperative to develop new aromatase-inhibiting/suppressing agents with lower toxicities and lower costs for breast cancer chemoprevention, especially in obese postmenopausal women. The expression of the aromatase gene, CYP19, is controlled in a tissuespecific manner by the alternate use of different promoters. In obese postmenopausal women, increased peripheral aromatase is primarily attributed to the activity of the glucocorticoid-stimulated promoter, PI.4, and the cAMPstimulated promoter, PII. In the present study, we show that methylseleninic acid (MSA), a second-generation selenium compound, can effectively suppress aromatase activation by dexamethasone, a synthetic glucocorticoid, and forskolin, a specific activator of adenylate cyclase. Unlike the action of aromatase inhibitors, MSA suppression of aromatase activation is not mediated via direct inhibition of aromatase enzymatic activity. Rather, it is attributable to a marked downregulation of promoters PI.4-and PII-specific aromatase mRNA expression, and thereby a reduction of aromatase protein. Considering the low-cost and low-toxicity nature of MSA, our findings provide a strong rationale for the further development of MSA as a breast cancer chemopreventive agent for obese postmenopausal women.

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Grape Seed Extract Is an Aromatase Inhibitor and a Suppressor of Aromatase Expression

Cited by 71 publications

References 54 publications

Enhanced expression of aromatase in p53-inactivated mammary epithelial cells

Enhanced expression of aromatase in p53-inactivated mammary epithelial cells

CCAAT/Enhancer Binding Protein δ Up-regulates Aromatase Promoters I.3/II in Breast Cancer Epithelial Cells

Methylseleninic acid is a novel suppressor of aromatase expression

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