Regulation of motility and protease expression in PKC-mediated induction of MCF-7 breast cancer cell invasiveness

M. D. Johnson, J. A. Torri, M. E. Lippman, R. B. Dickson

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

We investigated a potentially central role of protein kinase C (PKC) in controlling multiple pathways in breast cancer cell invasiveness. To do this we evaluated the ability of pharmacologic agents that alter PKC activity to regulate the behavior of the poorly invasive human breast cancer cell line MCF-7. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) produced a dramatic induction of the invasiveness of these cells (18-fold), an effect that concurrent treatment with the PKC inhibitor Bryostatin-1 was able to block. To characterize alterations in the cellular properties that might be responsible for these effects we measured the impact of these two agents on a number of processes thought to be important for invasiveness. The motility of the cells was first examined; it was markedly increased by treatment with TPA (20-fold) and again, Bryostatin-1 inhibited this stimulation. We next examined the expression of MMP-1,3,9,10, and 11 (matrix metalloproteinases), all of which have been shown to be PKC responsive in other systems. We found that the expression and secretion of MMP-9 were increased by at least 100- fold, though all of the enzyme secreted was in the latent form. Finally, the expression of both urokinase plasminogen activator (UPA) and its receptor (UPAR) were induced after TPA treatment by 8- and 7-fold, respectively. In conclusion, we have shown that stimulation of PKC activity markedly increases the invasiveness of MCF-7 cells, and that this change in behavior is correlated with a coordinated set of biochemical and cellular changes which are likely to contribute to this process. These data highlight the possible utility of PKC inhibitors such as Bryostatin-1 as anti-invasive and]or antimetastatic agents. Bryostatin-1 is currently in early clinical trials as an anticancer agent.

Original languageEnglish (US)
Pages (from-to)105-113
Number of pages9
JournalExperimental Cell Research
Volume247
Issue number1
DOIs
StatePublished - Feb 25 1999

Keywords

  • Breast cancer
  • Invasion
  • Motility
  • Protein kinase C
  • Proteinase

ASJC Scopus subject areas

  • Cell Biology

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