Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue

Chen, Shiuan; Ye, Jingjing; Kijima, Ikuko; Kinoshita, Yoshiyuki; Zhou, Dujin

doi:10.1016/j.jsbmb.2005.04.002

Cited by 39 publications

(29 citation statements)

References 27 publications

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“…In this study, we show that MLT actions on BAFs are not promoter-specific and suppress each of the three promoters expressed. This data correlates with what is observed in MCF-7 cells despite the subtle differences in modes of PII transcriptional activation by alternative transcription factors in the two different cell types [14,20]. Elevated levels of PI.4 in CAFs are due to elevated levels of class I cytokines and glucocorticoids within the tumor c Aromatase activity following PGE 2 (1 lM) stimulation alone or in combination with MLT (1 nM).…”

Section: Discussionsupporting

confidence: 83%

Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts

Knower¹,

To²,

Takagi

et al. 2012

Breast Cancer Res Treat

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The main biological active substance secreted by the pineal gland, melatonin (MLT), counteracts the effects of estrogens in breast cancer via exerting a number of its own oncostatic properties. Recent studies of postmenopausal women have identified that the major metabolite of MLT is statistically significantly associated with a lower risk of developing breast cancer. While MLT production decreases with age, breast cancer risk, however, increases with age and obesity. We hypothesize that MLT inhibits estrogen production in breast adipose fibroblasts (BAFs), the main local source of estrogen in breast tumors of postmenopausal women, by inhibiting transcription of the CYP19A1 gene that encodes the key enzyme aromatase. Normal BAFs were cultured from women undergoing breast reduction surgery, while breast cancer-associated fibroblasts (CAFs) were isolated from three women with estrogen receptor (ER) positive invasive ductal carcinomas. MTNR1A and MTNR1B receptor expression and CYP19A1 mRNA expression following MLT treatments were determined by qRT-PCR. BAFs express the G-protein coupled MLT receptors MTNR1A and MTNR1B with elevated levels of MTNR1A found in CAFs. Treatment of BAFs and CAFs with MLT resulted in significant suppression of CYP19A1 transcription and aromatase activity at pharmacological, physiological and sub-physiological concentrations. MLT suppression occurred through promoter-specific PI.4-, PI.3- and PII-derived CYP19A1 mRNA. Stimulation of CYP19A1 PII-mRNA and aromatase activity by prostaglandin E(2) (PGE(2)) were significantly attenuated by physiological doses of MLT. Lower levels of MLT in aging women may increase the risk of progressing ER-positive breast cancer through a decreased ability to suppress CYP19A1 expression and subsequent local estrogen production in BAFs/CAFs.

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Section: Discussionsupporting

confidence: 83%

Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts

Knower¹,

To²,

Takagi

et al. 2012

Breast Cancer Res Treat

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“…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). We have also been unable to detect a positive correlation between aromatase and ER status, which is in line with the observations by several other groups (Sasano et al 1994, Pasqualini & Chetrite 2005.…”

Section: Discussionmentioning

confidence: 50%

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

Singer

Fink-Retter²,

Gschwantler‐Kaulich³

et al. 2006

Endocr Relat Cancer

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The suppression of local estrogens levels is of key importance in the treatment of ER-positive breast cancer. Essentially all endocrine strategies act by either suppressing estrogen formation or competitively inhibiting receptor-binding in tumor cells. Nevertheless, little is still known about the local expression of aromatase and sulfotransferase which are the key modulators of intra-tumoral estrogen levels. We have performed immunohistochemostry to investigate the expression of aromatase and sulfotransferase in 42 samples obtained directly from malignant breast tumors, and compared it to biopsies obtained from uninvolved tissue in the vicinity of the invasion front, and to distant breast tissue. We found that aromatase was equally detectable in both tumor epithelial and stroma, but was mostly epithelial in non-malignant tissues (PZ0.00008, Fisher's exact test). Also, aromatase protein expression was significantly more common in tumoral stroma when compared with peritumoral and distant breast stroma (PZ0.00005, and P!0.00001 respectively). With the notable exception of cystosarcoma phylloides, sulfotransferase protein was detectable only in epithelial tissues, regardless of the location within the diseased breast. However, epithelial sulfotransferase was correlated with epithelial aromatase (rZ0.35461, PZ 0.0009, Spearman's r test) and with the epithelial ER status (rZ0.29313, PZ0.005). We have demonstrated a differential aromatase and sulfotransferase protein expression pattern that is dependent on the spatial relation to a malignant breast tumor. Our results indicate a net increase in intratumoral active estrogen levels through increased stromal aromatization, while physiological local inactivation by sulfotransferase activity remains essentially unchanged.

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“…Moreover, BRCA1 directly bound to the aromatase I.3/II promoter region, and hormonal stimulation of aromatase promoter activity decreased both BRCA1 levels and promoter binding. In malignant breast tumors, aromatase is expressed in both fibroblasts and malignant epithelial cells (29,30). Our data indicate that BRCA1 regulates aromatase expression in MCF7 and SKBR3 breast cancer cell lines, suggesting that BRCA1 deficiency in malignant breast tumors may lead to further aromatase overexpression in breast cancer.…”

Section: Discussionmentioning

confidence: 70%

BRCA1 Negatively Regulates the Cancer-Associated Aromatase Promoters I.3 and II in Breast Adipose Fibroblasts and Malignant Epithelial Cells

Lü

Chen

Lin

et al. 2006

The Journal of Clinical Endocrinology & Metabolism

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Context: Heterozygous mutations of the breast cancer susceptibility gene 1 (BRCA1) gene that lead to haploinsufficiency increase the risk of breast cancer. The underlying mechanism is unknown.Objective: Because excessive estrogen production increases the risk of breast cancer, we determined whether BRCA1 suppresses aromatase expression and thus local estrogen production in breast adipose fibroblasts (BAFs) and breast malignant epithelial cells by interacting with the cancer-associated promoter I.3/II region of the aromatase gene.Results: Treatment of BAFs with prostaglandin E 2 or a surrogate hormonal cocktail of dibutyryl (Bt 2 ) cAMP plus phorbol 12, 13-diacetate (PDA) significantly reduced BRCA1 levels and induced aromatase mRNA levels. Reduction of BRCA1 in BAFs and in MCF7 and SKBR3 malignant breast epithelial cells using small interfering RNA (siRNA) or small hairpin RNA significantly increased aromatase mRNA levels and enzyme activity. This effect of BRCA1 was mediated via selective inhibition of aromatase promoters I.3 and II that are up-regulated by prostaglandin E 2 or Bt 2 cAMPϩPDA treatment. Chromatin immunoprecipitation assays revealed that BRCA1 binds directly to the aromatase promoter I.3/II region and that BRCA1 binding is abolished by treatment with Bt 2 cAMPϩPDA. Conclusions

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Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue

Cited by 39 publications

References 27 publications

Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts

Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts

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

BRCA1 Negatively Regulates the Cancer-Associated Aromatase Promoters I.3 and II in Breast Adipose Fibroblasts and Malignant Epithelial Cells

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