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, Santanu Deb

研究成果: Review article査読

399 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)359-383
ページ数25
ジャーナルPharmacological Reviews
57
3
DOI
出版ステータスPublished - 2005 9

ASJC Scopus subject areas

  • 分子医療
  • 薬理学

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