title: Aromatase excess in cancers of breast, endometrium and ovary.
abstract: Pathogenesis and growth of three common women's cancers (breast, endometrium and ovary) are linked to estrogen. A single gene encodes the key enzyme for estrogen biosynthesis named aromatase, inhibition of which effectively eliminates estrogen production in the entire body. Aromatase inhibitors successfully treat breast cancer, whereas their roles in endometrial and ovarian cancers are less clear. Ovary, testis, adipose tissue, skin, hypothalamus and placenta express aromatase normally, whereas breast, endometrial and ovarian cancers overexpress aromatase and produce local estrogen exerting paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kb 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. In cancers of breast, endometrium and ovary, aromatase expression is primarly regulated by increased activity of the proximally located promoter I.3/II region. Promoters I.3 and II lie 215 bp from each other and are coordinately stimulated by PGE(2) via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE(2) secreted by malignant epithelial cells, PKC is also activated, and this potentiates cAMP-PKA-dependent induction of aromatase. Thus, inflammatory substances such as PGE(2) may play important roles in inducing local production of estrogen that promotes tumor growth.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA. s-bulun@northwestern.edu
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Meiling
authors.initials: M
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Youhong
authors.initials: Y
authors.lastname: Cheng
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: Emily
authors.initials: E
authors.lastname: Su
authors.forename: Erica
authors.initials: E
authors.lastname: Marsh
authors.forename: Amy
authors.initials: A
authors.lastname: Hakim
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Sanober
authors.initials: S
authors.lastname: Amin
authors.forename: Gonca
authors.initials: G
authors.lastname: Imir
authors.forename: Bilgin
authors.initials: B
authors.lastname: Gurates
authors.forename: Erkut
authors.initials: E
authors.lastname: Attar
authors.forename: Scott
authors.initials: S
authors.lastname: Reierstad
authors.forename: Joy
authors.initials: J
authors.lastname: Innes
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lin
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics
chemical_list: D001141:Aromatase