Regulation of aromatase expression in breast cancer tissue

S. E. Bulun, Z. Lin, H. Zhao, M. Lu, S. Amin, S. Reierstad, D. Chen

Research output: Chapter in Book/Report/Conference proceedingConference contribution

62 Scopus citations

Abstract

Epithelial-stromal interactions play key roles for aromatase expression and estrogen production in breast cancer tissue. Upregulated aromatase expression in breast fibroblasts increases the tissue concentration of estradiol (E2), which then activates a large number of carcinogenic genes via estrogen receptor-α (ERα) in malignant epithelial cells. This clinically pertains, since aromatase inhibitors (AIs) are the most effective hormonal treatment of ERα-positive breast tumors. A single gene encodes aromatase, the key enzyme in estrogen biosynthesis, the inhibition of which by an AI effectively eliminates E2 production. Since alternative promoters regulated by distinct signaling pathways control aromatase expression, it is possible to target these pathways and inhibit estrogen production in a tissue-selective fashion. We and others previously found that the majority of estrogen production in breast cancer tissue was accounted for by the aberrant activation of the proximal promoter I.3/II region. PGE2 that is secreted in large amounts by malignant breast epithelial cells is the most potent known natural inducer of this promoter region in breast adipose fibroblasts. Signaling effectors/transcriptional regulators that mediate PGE2 action include the activator pathways p38/CREB-ATF and JNK/jun and the inhibitory factor BRCA1 in breast adipose fibroblasts. Selective inhibition of this promoter region may treat breast cancer while permitting aromatase expression via alternative promoters in the brain and bone and thus obviate the key side effects of the current AIs. The signaling pathways that mediate the regulation of the promoter I.3/II region in undifferentiated fibroblasts in malignant breast tumors are reviewed.

Original languageEnglish (US)
Title of host publicationSteroid Enzymes and Cancer
PublisherBlackwell Publishing Inc.
Pages121-131
Number of pages11
ISBN (Print)9781573317450
DOIs
StatePublished - Feb 2009

Publication series

NameAnnals of the New York Academy of Sciences
Volume1155
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • ATF
  • Aromatase
  • BRCA-1
  • Breast cancer
  • CREB
  • Estrogen receptor-α, aromatase inhibitor
  • Jun kinase (JNK)
  • Prostaglandin E
  • p38 kinase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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