Aromatase excess in cancers of breast, endometrium and ovary.
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.
Bulun
Serdar E
SE
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
Chen
Dong
D
Lu
Meiling
M
Zhao
Hong
H
Cheng
Youhong
Y
Demura
Masashi
M
Yilmaz
Bertan
B
Martin
Regina
R
Utsunomiya
Hiroki
H
Thung
Steven
S
Su
Emily
E
Marsh
Erica
E
Hakim
Amy
A
Yin
Ping
P
Ishikawa
Hiroshi
H
Amin
Sanober
S
Imir
Gonca
G
Gurates
Bilgin
B
Attar
Erkut
E
Reierstad
Scott
S
Innes
Joy
J
Lin
Zhihong
Z
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
D001141:Aromatase