Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts

Chen, Dong; Reierstad, Scott; Lin, Zhihong; Lü, Meiling; Brooks, Chris; Li, Newton; Innes, Joy; Bulun, Serdar E.

doi:10.1158/0008-5472.can-06-4751

Cited by 74 publications

(62 citation statements)

References 61 publications

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“…Upon treatment with FSK and PMA, aromatase activity is induced via promoter II in SGBS cells. Consistent with previous reports in human primary preadipocytes, aromatase I.4-derived-mRNA was significantly down-regulated following FSK and PMA treatment [35]. Thus, the promoter switching which is observed in breast adipose tissue surrounding a tumour can Expression of total aromatase mRNA in SGBS cells following various incubation periods in adipogenic medium.…”

Section: Discussionsupporting

confidence: 91%

Characterisation of aromatase expression in the human adipocyte cell line SGBS

McInnes

Brown

Knower³

et al. 2008

Breast Cancer Res Treat

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Aromatase is a member of the cytochrome P450 superfamily of enzymes which catalyses the rate-limiting step in the biosynthesis of estrogens. A number of clinical studies have highlighted the importance of local estrogen production in adipose tissue. In particular, in the postmenopausal woman, the degree of her estrogenization is mainly determined by the extent of her adiposity and it is this extragonadal source of estrogen that likely contributes to breast cancer development and progression. The mechanisms regulating aromatase expression in adipose tissue however, have not been fully elucidated. In this study, we have characterised the expression of aromatase and its activity in a human preadipocyte cell strain, SGBS. Aromatase is expressed in SGBS cells and its expression and activity are strongly stimulated by forskolin (FSK) and phorbol 12-myristate-13-acetate (PMA) treatment. Consistent with this, FSK and PMA treatment also increased activation of the proximal aromatase promoter, promoter II. These findings mimic those that have previously been shown in isolated primary human preadipocytes. These data suggest that SGBS cells are a valuable model with which to further elucidate the mechanisms regulating aromatase expression, and therefore local estrogen synthesis in human adipose tissue.

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Section: Discussionsupporting

confidence: 91%

Characterisation of aromatase expression in the human adipocyte cell line SGBS

McInnes

Brown

Knower³

et al. 2008

Breast Cancer Res Treat

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“…It is likely that the CREs in promoter I.3/II, which can interact with members of the ATF/CREB family, may account for the rest of cAMP-dependent aromatase induction. PGE 2 is a potent inducer of aromatase in human breast adipose fibroblasts, endometriosis-derived stromal cells, and rat granulosa cells, which are dominantly regulated by the promoter I.3/II region (37)(38)(39)(40). Contrary to our expectations, PGE 2 showed little effect on aromatase expression in LSMCs.…”

Section: Discussioncontrasting

confidence: 99%

CCAAT/Enhancer Binding Protein β Regulates Aromatase Expression via Multiple and Novel Cis-Regulatory Sequences in Uterine Leiomyoma

Ishikawa¹,

Fencki²,

Marsh

et al. 2008

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context:Control of aromatase expression in uterine leiomyoma has significant clinical implications because aromatase inhibitors reduce tumor growth and associated irregular uterine bleeding. The mechanisms that regulate aromatase expression in leiomyoma are unknown. Objectives:We previously demonstrated that the cAMP-responsive proximal promoters I.3 and II regulate aromatase expression in vivo in uterine leiomyoma tissue. Here, we investigated the cellular and molecular mechanisms responsible for promoter I.3/II usage. Results:In smooth muscle cells isolated from leiomyoma (LSMCs), dibutyryl cAMP significantly induced aromatase mRNA and enzyme activity. Reporter constructs of promoter I.3/II deletion and site-directed mutants with selective disruption of cis-regulatory elements in the Ϫ517/Ϫ16 bp region revealed that five out of seven elements, including three CCAAT/enhancer binding protein (C/EBP) binding sites and two cAMP response elements, were essential for cAMP-induced promoter activity. EMSAs demonstrated that nuclear extracts from LSMCs contain complexes assembled on four of the five cis-elements, with C/EBP binding sites, including a novel Ϫ245/Ϫ231 bp sequence, clearly associating with C/EBP␤. Chromatin immunoprecipitation assays revealed that C/EBP␤ binds specifically to the promoter I.3/II region in intact cells. Dibutyryl cAMP significantly induced nuclear C/EBP␤ protein levels in LSMCs in a time-dependent manner. Conversely, knockdown of C/EBP␤ dramatically suppressed cAMP-induced aromatase mRNA and enzyme activity. R ecent clinical data indicate that aromatase plays a significant role in the pathophysiology of uterine leiomyomata because therapeutic targeting of aromatase effectively reduces the size of these tumors and associated symptoms such as uterine bleeding in premenopausal and perimenopausal women (1-4). Uterine leiomyomata, benign smooth muscle tumors originating from the uterus, are the most common solid tumors in reproductive age women and the most frequently reported indication for surgery in women. Leiomyoma generally causes abnormal uterine bleeding, menorrhagia, pressure-related symptoms, and recurrent pregnancy loss. Abnormal uterine bleeding represents the major complaint in women and is the primary indication for surgical intervention (5). Each leiomyoma represents a monoclonal proliferation of a transformed myocyte derived from myometrium (6). Although the pathogenesis of leiomyoma transformation from myometrium remains unknown, laboratory and

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“…In the breast adipose tissue, aromatase is mainly expressed in the BAFs and is undetectable in mature, lipidfilled adipocytes (1,51,54). In BCa the BAFs provide structural support for tumors, whereas the malignant epithelial cells secrete factors such as PGE 2 and cytokines that act on the BAFs, preventing their differentiation and thereby increasing aromatase expression and local estrogen synthesis (1,41,52,55). The rise in aromatase in the BAFs surrounding a breast tumor is accompanied by a switch in aromatase promoter usage from promoter I.4, which is normally used in adipose tissue to promoters I.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, calcitriol itself is known to cause the differentiation of 3T3-L1 cells into mature adipocytes (56). Therefore, we hypothesize that calcitriol decreases aromatase expression in the preadipocytes/BAFs by three mechanisms: 1) inducing the differentiation of preadipocytes into mature adipocytes with reduced aromatase expression, 2) directly suppressing aromatase transcription through promoter II in the tumor-adjacent preadipocytes, and 3) an indirect mechanism of decreasing the secretion by the malignant epithelial cells of PGE 2 , which is a major inducer of aromatase transcription through promoter II/ I.3 in the surrounding BAFs (1,53,55).…”

Section: Discussionmentioning

confidence: 99%

Tissue-Selective Regulation of Aromatase Expression by Calcitriol: Implications for Breast Cancer Therapy

et al. 2010

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Aromatase, the enzyme that catalyzes estrogen synthesis, is critical for the progression of estrogen receptor-positive breast cancer (BCa) in postmenopausal women. We show that calcitriol, the hormonally active form of vitamin D, regulates the expression of aromatase in a tissue-selective manner. Calcitriol significantly decreased aromatase expression in human BCa cells and adipocytes and caused substantial increases in human osteosarcoma cells (a bone cell model exhibiting osteoblast phenotype in culture) and modest increases in ovarian cancer cells. Calcitriol administration to immunocompromised mice bearing human BCa xenografts decreased aromatase mRNA levels in the tumors and the surrounding mammary adipose tissue but did not alter ovarian aromatase expression. In BCa cells, calcitriol also reduced the levels of prostaglandins (PGs), major stimulators of aromatase transcription, by suppressing the expression of cyclooxygenase-2 (which catalyzes PG synthesis) and increasing that of 15-hydroxyprostaglandin dehydrogenase (which catalyzes PG degradation). The mechanism of aromatase down-regulation by calcitriol in BCa cells is therefore 2-fold: a direct repression of aromatase transcription via promoter II through the vitamin D-response elements identified in this promoter and an indirect suppression by reducing the levels of PGs. Combinations of calcitriol with three different aromatase inhibitors (AIs) caused enhanced inhibition of BCa cell growth. The combination of calcitriol and an AI may have potential benefits for BCa therapy. In addition to augmenting the ability of AIs to inhibit BCa growth, calcitriol acting as a selective aromatase modulator that increases aromatase expression in bone would reduce the estrogen deprivation in bone caused by the AIs, thus ameliorating the AI-induced side effect of osteoporosis.

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Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts

Cited by 74 publications

References 61 publications

Characterisation of aromatase expression in the human adipocyte cell line SGBS

Characterisation of aromatase expression in the human adipocyte cell line SGBS

CCAAT/Enhancer Binding Protein β Regulates Aromatase Expression via Multiple and Novel Cis-Regulatory Sequences in Uterine Leiomyoma

Tissue-Selective Regulation of Aromatase Expression by Calcitriol: Implications for Breast Cancer Therapy

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