Tissue-specific promoters regulate aromatase cytochrome P450 expression

Simpson, Evan R.; Mahendroo, Mala; Means, Gary; Kilgore, Michael W.; Corbin, C. J.; Mendelson, Carole R.

doi:10.1016/0960-0760(93)90235-o

Cited by 126 publications

(49 citation statements)

References 36 publications

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“…The aromatase enzyme consists of a complex containing a cytochrome P-450 protein as well as the flavoprotein NADPH cytochrome P-450 reductase (Simpson et al 1997). The gene coding for the cytochrome P-450 protein (P-450 AROM) exceeds 70 kb and is the largest of the cytochrome P-450 family (Simpson et al 1993). The cDNA of the aromatase gene contains 3.4 kb and encodes a polypeptide of 503 amino acids with a molecular weight of 55 kDa.…”

Section: Physiology and Regulation Of Aromatasementioning

confidence: 99%

“…Recent studies indicate that the transcription of the aromatase gene is highly regulated (Simpson et al 1989(Simpson et al , 1993(Simpson et al , 1997. The first exon of the aromatase gene is transcribed into aromatase message but not translated into protein.…”

Section: Physiology and Regulation Of Aromatasementioning

confidence: 99%

“…Enhancers which react with upstream elements of these alternate exons markedly stimulate the rate of transcription of the aromatase gene. Thus, each tissue can regulate the amount of aromatase transcribed in a highly specific manner (Simpson et al 1993).…”

Section: Physiology and Regulation Of Aromatasementioning

confidence: 99%

See 2 more Smart Citations

Use of aromatase inhibitors in breast carcinoma.

Santen¹,

Harvey²

1999

Endocrine-Related Cancer

146

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Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack crossresistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormonedependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older Endocrine-Related Cancer (1999) 6 75-92 patients and quite possibly in chemoprevention trials of breast cancer.

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Section: Physiology and Regulation Of Aromatasementioning

confidence: 99%

Section: Physiology and Regulation Of Aromatasementioning

confidence: 99%

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Use of aromatase inhibitors in breast carcinoma.

Santen¹,

Harvey²

1999

Endocrine-Related Cancer

146

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“…Further, upstream of exon II, a number of alternative first exons that are differently spliced into distinct 5′-untranslated regions are described (fig. 1) [4, 5, 6]. In addition, up to now nine different transcriptional start sides with individual promoters permitting tissue-specific regulation of expression are known [6].…”

Section: The Genetic Structure Of P450arom: Cyp19 Genementioning

confidence: 99%

The Aromatase Cytochrome P-450 and Its Clinical Impact

Meinhardt

Mullis

2002

Horm Res Paediatr

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Cytochrome P-450 aromatase (P450arom), the key enzyme for estrogen biosynthesis, is encoded by a single gene, namely the CYP19 gene, localized on 15q21.2. The human CYP19 gene spans about 123 kb with a coding region of 9 exons (about 30 kb, exon II–exon X). Although there are a number of alternative first exons and nine different transcriptional start sides with individual promoters that permit tissue-specific regulation of expression, the protein expressed in these various tissue sites (placenta, adipose tissue, brain, bone, ovary, etc.) is the same regardless of the promoter used. P450arom catalyzes the conversion of testosterone to estradiol, of androstenedione to estrone, and of 16α-hydroxylated dehydroepiandrosterone to estriol. As not only androgens but also estrogens are of importance, particularly in the male pubertal development, including bone changes which were classically considered mostly androgen dependent, the features of the aromatase deficiency syndrome in affected boys and girls as well as adult males and females are discussed. There is growing awareness that androgens and estrogens have general metabolic roles that reach far beyond reproductive processes. For instance, estrogen has a significant impact on carbohydrate and lipid metabolism, vascular function, and arteriosclerosis. In addition, extragonadal estrogen biosynthesis plays an important but often underestimated physiological and pathophysiological role, for example in breast cancer and endometriosis. Based on that knowledge, progress has been made as far as treatment and follow-up of these disorders are concerned. In addition, there is a focus on the treatment of children suffering from a lack of P450arom activity.

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“…Remarkably, the regulation of aromatase appears to be different in different tissues. Several tissue-specific promoter regions have been identified upstream from the CYP19 gene [65][66][67]. Promoter PI.1 is the major promoter used in placental tissues and is the farthest upstream.…”

Section: Selective Modulation Of Aromatasementioning

confidence: 99%

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

Jordan¹,

Brodie²

2007

Steroids

259

183

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The enthusiasm with which the clinical community has embraced the use of antiestrogenic therapy to treat breast cancer is based upon the proven record of success that first the nonsteroidal antiestrogen tamoxifen and then the aromatase inhibitor have demonstrated in clinical trial. The reasons for the enthusiasm are obvious. Antihormonal therapy, particularly aromatase inhibition to create a "no estrogen state" in the postmenopausal breast cancer patient is effective, saves women's lives, is contributing successfully to reducing the national mortality from breast cancer, is relatively cheap and has fewer side effects and easy administration (oral) than any other anticancer strategy. However, the successful application of a therapeutic strategy to block the known growth stimulation property of estrogen in breast cancer was not greeted with such enthusiasm 40 years ago.Estrogen is essential for life. Without the critical role of estrogenic steroids, reproduction would not be possible. Based on emerging knowledge from laboratory studies, the value of modulating the steroid environment during the menstrual cycle was advanced to clinical testing during the 1950's as a means of oral contraception. The results of these studies were to change society forever.The Worcester Foundation for Experimental Biology is the place where Gregory Pincus established the scientific principles necessary to propose clinical testing of the oral contraceptive and M.C. Chang subsequently established the first protocols to perform in vitro fertilization. Simply stated, the Worcester Foundation was, at that time, the world center for steroid endocrinology and reproductive biology. Over the years, hundreds of scientists have trained at the Foundation and subsequently spread their knowledge throughout the world [1]. However, fashions in research change and new opportunities emerge.In 1971, President Nixon made a national commitment to seek a cure for cancer by signing the National Cancer Act. Mahlon Hoagland, the President of the Worcester Foundation, responded to the initiative by appointing Professor Elwood V. Jensen, Director of the Ben May Cancer Research Laboratory at the University of Chicago, to be a member of the Foundation's Scientific Advisory Board. Jensen had discovered the estrogen receptor (ER) as the putative mechanism of estrogen action in its target tissues [2]. The known link between estrogen and breast cancer suggested that "antiestrogenic strategies" might have potential as therapeutic Correspondence to: V. Craig Jordan, v.craig.jordan@fccc.edu. Present Address: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be d...

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Tissue-specific promoters regulate aromatase cytochrome P450 expression

Cited by 126 publications

References 36 publications

Use of aromatase inhibitors in breast carcinoma.

Use of aromatase inhibitors in breast carcinoma.

The Aromatase Cytochrome P-450 and Its Clinical Impact

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

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