Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, invasion and matrix metalloproteinase expression

BMC Cancer. 2006 Jul 10;6:181. doi: 10.1186/1471-2407-6-181.

Abstract

Background: Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the formation of prostaglandins. The inducible isoform of COX (COX-2) is highly expressed in aggressive metastatic breast cancers and may play a critical role in cancer progression (i.e. growth and metastasis). However, the exact mechanism(s) for COX-2-enhanced metastasis has yet to be clearly defined. It is well established that one of the direct results of COX-2 action is increased prostaglandin production, especially prostaglandin E2 (PGE2). Here, we correlate the inhibition of COX-2 activity with decreased breast cancer cell proliferation, migration, invasion and matrix metalloproteinase (MMP) expression.

Methods: Breast cancer cells (Hs578T, MDA-MB-231 and MCF-7) were treated with selective COX-2 inhibitors (NS-398 and Niflumic acid, NA). Cell proliferation was measured by staining with erythrosin B and counting the viable cells using a hemacytometer. Cell migration and invasion were measured using migration and invasion chamber systems. MMP expression was determined by enzyme immunoassay (secreted protein) and real-time quantitative polymerase chain reaction (mRNA).

Results: Our results show that there is a decline in proliferation, migration and invasion by the Hs578T and MDA-MB-231 breast cancer cell lines in the presence of either low concentrations (1 microM or lower) NA or NS-398. We also report that MMP mRNA and protein expression by Hs578T cells is inhibited by NS-398; there was a 50% decrease by 100 muM NS-398. PGE2 completely reversed the inhibitory effect of NS-398 on MMP mRNA expression.

Conclusion: Our data suggests that COX-2-dependent activity is a necessary component for cellular and molecular mechanisms of breast cancer cell motility and invasion. COX-2 activity also modulates the expression of MMPs, which may be a part of the molecular mechanism by which COX-2 promotes cell invasion and migration. The studies suggest that COX-2 assists in determining and defining the metastatic signaling pathways that promote the breast cancer progression to metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Cyclooxygenase 2 Inhibitors / therapeutic use*
  • Dinoprostone / pharmacology
  • Gene Expression Profiling
  • Humans
  • Matrix Metalloproteinases / metabolism*
  • Membrane Proteins / metabolism
  • Neoplasm Invasiveness*
  • RNA, Messenger / metabolism
  • Tumor Cells, Cultured

Substances

  • Cyclooxygenase 2 Inhibitors
  • Membrane Proteins
  • RNA, Messenger
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Matrix Metalloproteinases
  • Dinoprostone