Aromatase excess in cancers of breast, endometrium and ovary

Serdar E. Bulun, Dong Chen, Meiling Lu, Hong Zhao, Youhong Cheng, Masashi Demura, Bertan Yilmaz, Regina Martin, Hiroki Utsunomiya, Steven Thung, Emily Su, Erica Marsh, Amy Hakim, Ping Yin, Hiroshi Ishikawa, Sanober Amin, Gonca Imir, Bilgin Gurates, Erkut Attar, Scott ReierstadJoy Innes, Zhihong Lin

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)

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 PGE2 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.

Original languageEnglish
Pages (from-to)81-96
Number of pages16
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume106
Issue number1-5
DOIs
Publication statusPublished - 2007 Aug

Keywords

  • Aromatase
  • Aromatase excess syndrome
  • Aromatase inhibitor
  • Aromatase overexpression
  • Breast cancer
  • Endometrial cancer
  • Endometriosis
  • Endometrium
  • Estrogen
  • Estrogen biosynthesis
  • Fibroids
  • Gain-of-function mutations
  • Gynecomastia
  • Uterine leiomyomata
  • Uterus

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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