Prostaglandin E2 induces breast cancer-related aromatase promoters via activation of p38 and c-jun NH2-terminal kinase in adipose fibroblasts

Dong Chen*, Scott Reierstad, Zhihong Lin, Meiling Lu, Chris Brooks, Newton Li, Joy Innes, Serdar E. Bulun

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


Aromatase is the key enzyme for estrogen biosynthesis. A distal promoter, PI.4, maintains baseline levels of aromatase in normal breast adipose tissue. In contrast, malignant breast epithelial cells secrete prostaglandin E2 (PGE2), which stimulates aromatase expression via proximal promoters PI.3/PII in a cyclic AMP (cAMP)- and protein kinase C (PKC)-dependent manner in adjacent breast adipose fibroblasts (BAF), leading to increased local concentrations of estrogen. Although an effective treatment for breast cancer, aromatase inhibitors indiscriminately abolish estrogen synthesis in all tissues, causing major side effects. To identify drug targets to selectively block aromatase and estrogen production in breast cancer, we investigated PGE 2-stimulated signaling pathways essential for aromatase induction downstream of cAMP and PKC in human BAFs. Here, we show that PGE2 or its surrogate hormonal mixture dibutyryl cAMP (Bt2cAMP) + phorbol diacetate (PDA) stimulated the p38, c-jun NH2-terminal kinase (JNK)-1, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathways. Inhibition or small interfering RNA-mediated knockdown of p38 or JNK1, but not ERK, inhibited PGE2- or Bt2cAMP + PDA-induced aromatase activity and expression via PI.3/PII. Conversely, overexpression of wildtype p38α or JNK1 enhanced PGE2- stimulated aromatase expression via PII. PGE2 or Bt2cAMP + PDA stimulated c-Jun and activating transcription factor-2 (ATF2) phosphorylation and binding to the PI.3/PII region. Specific activation of protein kinase A (PKA) or EPAC with cAMP analogues stimulated p38 and JNK1; however, only PKA-activating cAMP analogues induced aromatase expression. The PKC activator PDA effectively stimulated p38 and JNK1 phosphorylation but not aromatase expression. Taken together, PGE2 activation of p38 and JNK1 via PKA and PKC is necessary for aromatase induction in BAFs, and p38 and JNK1 are potential new drug targets for tissue-specific ablation of aromatase expression in breast cancer.

Original languageEnglish (US)
Pages (from-to)8914-8922
Number of pages9
JournalCancer Research
Issue number18
StatePublished - Sep 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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