The PPARgamma Antagonist T0070907 Suppresses Breast Cancer Cell Proliferation and Motility via Both PPARgamma-dependent and -Independent Mechanisms

Anticancer Res. 2011 Mar;31(3):813-23.

Abstract

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) is overexpressed in many types of cancer, including breast cancer, and it is regulated by ligand binding and post-translational modifications. It was previously demonstrated that endogenous transactivation promotes an aggressive phenotype of malignant breast cells. This study examines whether selective antagonism of PPARγ with T0070907 is a potential strategy for breast cancer therapy.

Materials and methods: PPARγ activation was inhibited using both pharmacological and molecular approaches and proliferation, apoptosis, migration and invasion were measured in MDA-MB-231 and MCF-7 breast cancer cells.

Results: T0070907 treatment inhibited proliferation, invasion and migration but did not significantly affect apoptosis. Molecular inhibition using a dominant negative (Δ462) receptor yielded similar results. T007 also mediated a dose-dependent decrease in phosphorylation of PPARγ, and its ability to bind to DNA, and may directly affect mitogen-activated protein kinase signaling.

Conclusion: These data indicate that inhibiting endogenous PPARγ signaling may be a promising new approach to breast cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • DNA, Neoplasm / metabolism
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Dominant / genetics
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation / genetics
  • Neoplasm Invasiveness
  • PPAR gamma / antagonists & inhibitors*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Phenotype
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use*
  • Response Elements / genetics
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects

Substances

  • Benzamides
  • DNA, Neoplasm
  • PPAR gamma
  • Pyridines
  • T 0070907
  • Focal Adhesion Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases