title: Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment.
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.
authors.affiliation: Division of Reproductive Biology Research, Department of Obstetric and Gynecology, Northwestern University, Chicago, IL 60611, USA. s-bulun@northwestern.edu
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lin
authors.forename: Gonca
authors.initials: G
authors.lastname: Imir
authors.forename: Sanober
authors.initials: S
authors.lastname: Amin
authors.forename: Masashi
authors.initials: M
authors.lastname: Demura
authors.forename: Bertan
authors.initials: B
authors.lastname: Yilmaz
authors.forename: Regina
authors.initials: R
authors.lastname: Martin
authors.forename: Hiroki
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: Steven
authors.initials: S
authors.lastname: Thung
authors.forename: Bilgin
authors.initials: B
authors.lastname: Gurates
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Tamura
authors.forename: David
authors.initials: D
authors.lastname: Langoi
authors.forename: Santanu
authors.initials: S
authors.lastname: Deb
mesh_terms: D000818:Animals; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D010049:Ovarian Diseases / Q000201:enzymology* / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D047072:Aromatase Inhibitors; D004967:Estrogens; D001141:Aromatase