Jund and junb integrate prostaglandin e2 activation of breast cancer-associated proximal aromatase promoters

Dong Chen*, Scott Reierstad, Feng Fang, Serdar E. Bulun

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Aromatase is the key enzyme in estrogen biosynthesis. Normal breast adipose tissue expresses low levels of aromatase via the distal promoter I.4. Breast adipose tissue surrounding a tumor exhibits excessive aromatase expression controlled by proximal aromatase promoters I.3/II, leading to high local levels of estrogen and breast cancer progression. Prostaglandin E2 (PGE2) secreted by malignant breast epithelial cells activates breast cancer-associated aromatase promoters I.3/II, but silences promoter I.4, in cultured human breast adipose fibroblasts (BAF). The c-Jun N-terminal kinase 1 and p38α mitogen activated protein kinases are necessary for PGE2 activation of aromatase promoters I.3/II; thus, we examined the roles of downstream targets, c-Jun, JunB, JunD, and activating transcription factor 2, in PGE2-mediated regulation of aromatase expression in BAF. PGE2 induced JunB and JunD protein expression through protein kinase A and protein kinase C, respectively. JunB or JunD knockdown by small interfering RNA markedly reduced PGE2-induced total aromatase mRNA level and enzyme activity via promoters I.3/II. JunB knockdown also abrogated JunD expression. JunB stimulated, whereas JunD inhibited, aromatase promoter I.4 activity. Activating transcription factor 2 knockdown did not affect promoter-specific or total aromatase mRNA levels. c-Jun knockdown increased promoter I.4-specific and PGE2-induced promoters I.3/II-specific aromatase mRNA levels, leading to enhanced PGE2-induced total aromatase mRNA level and enzyme activity.JunD,c-Jun,and JunB bound to a CRE(-211/-199) essential for PGE2 induction of aromatase promoters I.3/II. Taken together, JunD and c-Jun repress aromatase promoter I.4. JunD mediates, whereas c-Jun modulates, PGE2 activation of aromatase promoters I.3/II via CRE(-211/-199). JunB also activates aromatase promoters I.3/II by maintaining JunD expression. Targeting JunD may abolish aromatase expression selectively in breast cancer tissue.

Original languageEnglish (US)
Pages (from-to)767-775
Number of pages9
JournalMolecular Endocrinology
Volume25
Issue number5
DOIs
StatePublished - May 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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