Aromatase excess in cancers of breast, endometrium and ovary
Author
SU, Emily
Attar, Erkut
UTSUNOMIYA, Hiroki
THUNG, Steven
MARSH, Erica
HAKIM, Amy
YIN, Ping
ISHIKAWA, Hiroshi
AMIN, Sanober
IMIR, Gonca
GURATES, Bilgin
REIERSTAD, Scott
INNES, Joy
LIN, Zhihong
BULUN, Serdar E.
CHEN, Dong
LU, Meiling
ZHAO, Hong
CHENG, Youhong
DEMURA, Masashi
YILMAZ, Bertan
MARTIN, Regina
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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 11 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 PGE2 secreted by malignant epithelial cells, PKC is also activated, and this potentiates cAMP-PKA-dependent induction of aromatase. Thus, inflammatory substances such as PGE2 may play important roles in inducing local production of estrogen that promotes tumor growth. (C) 2007 Elsevier Ltd. All rights reserved.
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