Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• PPARγ agonists show limited anticancer efficacy in clinical trials.
• HDAC overexpression hinders PPARγ agonist activity through transcriptional and post-translational mechanisms.

Purpose of the Study:

• To investigate the mechanism of resistance to PPARγ agonists in cancer.
• To evaluate the efficacy of combining PPARγ agonists with HDAC inhibitors for cancer treatment.

Main Methods:

• Assessed PPARG, HDAC1, and HDAC2 expression in relation to patient prognosis.
• Utilized in vitro cell culture models of triple-negative and ERα-positive breast cancer.
• Employed combination therapy with PPARγ agonists and HDAC inhibitors in preclinical models.
• Conducted pharmacokinetic studies and evaluated combination therapy in a mouse model of triple-negative breast cancer.

Main Results:

• HDAC overexpression was found to blunt anti-proliferative and anti-angiogenic responses to PPARγ agonists.
• Combination therapy with HDAC inhibitors restored sensitivity to PPARγ agonists in resistant breast cancer cells.
• Synergistic effects were observed in ERα-positive cells, overcoming ERα-mediated interference.
• The combination of rosiglitazone and LBH589 demonstrated superior efficacy and a favorable safety profile in a triple-negative breast cancer mouse model.

Conclusions:

• HDAC inhibitors can overcome resistance to PPARγ agonists by neutralizing HDAC-mediated suppression.
• Combination therapy represents a promising strategy for treating aggressive breast cancer subtypes, including triple-negative and endocrine-refractory breast cancer.
• This approach addresses historical observations of de novo resistance to PPARγ agonist monotherapy.