Differential regulation of the aggressive phenotype of inflammatory breast cancer cells by prostanoid receptors EP3 and EP4

Fredika M. Robertson, Ann Marie Simeone, Anthony Lucci, John S. McMurray, Sukhen Ghosh, Massimo Cristofanilli

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

BACKGROUND: Although inflammatory breast cancer (IBC) is recognized as the most lethal variant of locally advanced breast cancer, few molecular signatures of IBC have been identified that can be used as targets to develop therapeutics that effectively inhibit the aggressive phenotype displayed by IBC tumors. METHODS: Real-time polymerase chain reaction analysis, Western blot analysis, modified Boyden chamber invasion assays, vasculogenic mimicry (VM) assays, and gelatin zymography were used in the current studies. Agonists and antagonists of the prostanoid receptors EP3 and EP4 and of EP4 short-hairpin RNA (shRNA) knockdown approaches were used as tools to assess the role of prostanoid receptors EP3 and EP4 in the regulation of specific biologic activities of IBC cells. RESULTS: The current studies revealed that the IBC breast cancer cell lines SUM149 and SUM190 express high levels of cyclooxygenase-2 messenger RNA and protein, produce abundant levels of prostaglandin E2, and produce both EP3 and EP4 receptor proteins. Studies using the EP4 antagonist GW627368X and shRNA molecular knockdown approaches revealed a role for EP4 in regulating invasion of IBC cells. EP3, but not EP4, regulated the ability of SUM149 cells to undergo VM, which is the ability to form capillary-like structures, a characteristic exhibited by very aggressive tumor types. Inhibition of VM by sulprostone was associated with an inhibition of matrix metalloprotease-2 (MMP-2) enzyme activity. CONCLUSIONS: The prostanoid receptors EP3 and EP4 differentially regulate activities exhibited by IBC cells that have been associated with the aggressive phenotype of this lethal variant of breast cancer. Whereas EP4 regulates invasion, EP3 regulates VM and the associated increased MMP-2 enzyme activity.

Original languageEnglish (US)
Pages (from-to)2806-2814
Number of pages9
JournalCancer
Volume116
Issue numberSUPPL. 11
DOIs
StatePublished - Jun 1 2010

Keywords

  • Cyclooxygenase-2
  • Inflammatory breast cancer
  • Invasion
  • Matrix metalloprotease-2
  • Prostaglandin E
  • Prostanoid receptor 3
  • Prostanoid receptor 4
  • Vasculogenic mimicry

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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