JunD and JunB integrate prostaglandin E2 activation of breast cancer-associated proximal aromatase promoters.

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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2)-mediated regulation of aromatase expression in BAF. PGE(2) 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 PGE(2)-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 PGE(2)-induced promoters I.3/II-specific aromatase mRNA levels, leading to enhanced PGE(2)-induced total aromatase mRNA level and enzyme activity. JunD, c-Jun, and JunB bound to a CRE(-211/-199) essential for PGE(2) induction of aromatase promoters I.3/II. Taken together, JunD and c-Jun repress aromatase promoter I.4. JunD mediates, whereas c-Jun modulates, PGE(2) 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.

• Authors: Dong Chen, Scott Reierstad, Feng Fang, Serdar E Bulun
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 25 Issue 5 Pg. 767-75 (May 2011) ISSN: 1944-9917 [Electronic] United States
• PMID: 21393445 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-jun
• Luciferases, Renilla
• Aromatase
• Dinoprostone

Topics

• Adipose Tissue (metabolism, pathology)
• Aromatase (genetics, metabolism)
• Base Sequence
• Breast Neoplasms (metabolism, pathology)
• Dinoprostone (metabolism)
• Female
• Fibroblasts (metabolism)
• Gene Components
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Humans
• Luciferases, Renilla (biosynthesis, genetics)
• Protein Binding
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Regulatory Elements, Transcriptional
• Transcription, Genetic
• Transcriptional Activation