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Research ArticleArticle

Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment

Serdar E. Bulun, Zhihong Lin, Gonca Imir, Sanober Amin, Masashi Demura, Bertan Yilmaz, Regina Martin, Hiroki Utsunomiya, Steven Thung, Bilgin Gurates, Mitsutoshi Tamura, David Langoi and Santanu Deb
Pharmacological Reviews September 2005, 57 (3) 359-383; DOI: https://doi.org/10.1124/pr.57.3.6
Serdar E. Bulun
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Zhihong Lin
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Gonca Imir
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Sanober Amin
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Masashi Demura
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Bertan Yilmaz
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Regina Martin
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Hiroki Utsunomiya
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Steven Thung
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Bilgin Gurates
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Mitsutoshi Tamura
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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David Langoi
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Santanu Deb
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
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Abstract

A single gene encodes the key enzyme for estrogen biosynthesis termed aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress aromatase and produce local estrogen that exerts paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. Three mechanisms are responsible for aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of aromatase in many tissues.

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Pharmacological Reviews: 57 (3)
Pharmacological Reviews
Vol. 57, Issue 3
1 Sep 2005
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Research ArticleArticle

Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment

Serdar E. Bulun, Zhihong Lin, Gonca Imir, Sanober Amin, Masashi Demura, Bertan Yilmaz, Regina Martin, Hiroki Utsunomiya, Steven Thung, Bilgin Gurates, Mitsutoshi Tamura, David Langoi and Santanu Deb
Pharmacological Reviews September 1, 2005, 57 (3) 359-383; DOI: https://doi.org/10.1124/pr.57.3.6

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Research ArticleArticle

Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment

Serdar E. Bulun, Zhihong Lin, Gonca Imir, Sanober Amin, Masashi Demura, Bertan Yilmaz, Regina Martin, Hiroki Utsunomiya, Steven Thung, Bilgin Gurates, Mitsutoshi Tamura, David Langoi and Santanu Deb
Pharmacological Reviews September 1, 2005, 57 (3) 359-383; DOI: https://doi.org/10.1124/pr.57.3.6
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  • Article
    • Abstract
    • I. Introduction
    • II. Aromatase and Breast Cancer
    • III. Aromatase and Endometriosis
    • IV. Aromatase and Endometrial Cancer
    • V. Aromatase and Uterine Fibroids (Leiomyomata)
    • VI. Aromatase Excess Syndrome
    • VII. Conclusions Regarding Aromatase Overexpression in Estrogen-Dependent Human Disease
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