Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells

Eugene P. Toy, Tiffany Lamb, Masoud Azodi, William J. Roy, Ho Hyung Woo, Setsuko K Chambers

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The c-fms proto-oncogene encoded CSF-1 receptor and its ligand represent a feedback loop, which in a paracrine manner, is well known to promote spread of breast cancers. The role of the autocrine feedback loop in promotion of breast tumor behavior, in particular in vitro, is less well understood. The physiologic stimulation of c-fms expression by glucocorticoids (GCs) in vitro and in vivo magnifies the tumor promoting effect seen in these cells from activated c-fms signaling by CSF-1. Targeted molecular therapy against c-fms could therefore abrogate both complementary feedback loops. Using breast cancer cells endogenously co-expressing receptor and ligand, we used complementary approaches to inhibit c-fms expression and function within this autocrine pathway in the context of GC stimulation. Silencing RNA (shRNA), antisense oligonucleotide therapy (AON), and inhibition of c-fms signaling, were all used to quantitate inhibition of GC-stimulated adhesion, motility, and invasion of human breast cancer cells in vitro. shRNA to c-fms downregulated GC-stimulated c-fms mRNA by fourfold over controls, correlating with over twofold reduction in cellular invasiveness. AON therapy was also able to inhibit GC stimulation of c-fms mRNA, and resulted in threefold less invasiveness and 1.5 to 2-fold reductions in adhesion and motility. Finally, the small-molecule c-fms inhibitor Ki20227 was able to decrease in a dose-response manner, breast cancer cell invasion by up to fourfold. Inhibition of this receptor/ligand pair may have clinical utility in inhibition of the autocrine as well as the known paracrine interactions in breast cancer, thus further supporting use of targeted therapies in this disease.

Original languageEnglish (US)
Pages (from-to)411-419
Number of pages9
JournalBreast Cancer Research and Treatment
Volume129
Issue number2
DOIs
StatePublished - Sep 2011

Fingerprint

fms Genes
Glucocorticoids
Breast Neoplasms
Phenotype
Neoplasms
Antisense Oligonucleotides
Ligands
Small Interfering RNA
Macrophage Colony-Stimulating Factor Receptors
Molecular Targeted Therapy
Messenger RNA
Macrophage Colony-Stimulating Factor
Therapeutics
RNA Interference
Inhibition (Psychology)
Down-Regulation

Keywords

  • Breast cancer
  • c-fms
  • Glucocorticoids
  • Invasion
  • Proto-oncogene

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells. / Toy, Eugene P.; Lamb, Tiffany; Azodi, Masoud; Roy, William J.; Woo, Ho Hyung; Chambers, Setsuko K.

In: Breast Cancer Research and Treatment, Vol. 129, No. 2, 09.2011, p. 411-419.

Research output: Contribution to journalArticle

Toy, Eugene P. ; Lamb, Tiffany ; Azodi, Masoud ; Roy, William J. ; Woo, Ho Hyung ; Chambers, Setsuko K. / Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells. In: Breast Cancer Research and Treatment. 2011 ; Vol. 129, No. 2. pp. 411-419.
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