The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms.

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.

• Authors: Yekaterina Y Zaytseva, Natalie K Wallis, R Chase Southard, Michael W Kilgore
• Journal: Anticancer research (Anticancer Res) Vol. 31 Issue 3 Pg. 813-23 (Mar 2011) ISSN: 1791-7530 [Electronic] Greece
• PMID: 21498701 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Apoptosis (drug effects)
• Benzamides (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, enzymology, genetics, 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, genetics, metabolism)
• Phenotype
• Phosphorylation (drug effects)
• Protein Binding (drug effects)
• Pyridines (pharmacology, therapeutic use)
• Response Elements (genetics)
• Signal Transduction (drug effects)
• Transcription, Genetic (drug effects)