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.

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@article{Bulun2007AromataseEI, title={Aromatase excess in cancers of breast, endometrium and ovary.}, author={Serdar E. Bulun and Dong Chen and Meiling Lu and Hong Zhao and Youhong Cheng and Masashi Demura and Bertan Yilmaz and Regina Martin and Hiroki Utsunomiya and Steven Thung and Emily J. Su and Erica E. Marsh and Amy Hakim and Ping Yin and Hiroshi Ishikawa and Sanober A Amin and Gonca Imir and Bilgin Gurates and Erkut Attar and Scott Reierstad and Joy E Innes and Zhiyue Lin}, journal={The Journal of steroid biochemistry and molecular biology}, year={2007}, volume={106 1-5}, pages={81-96} }