High expression of apoptosis protein (Api-5) in chemoresistant triple-negative breast cancers: an innovative target

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Triple-negative breast cancer (TNBC) often exhibits chemoresistance, posing a significant clinical challenge.
• Anti-apoptotic protein-5 (API-5) is a survival protein that inhibits apoptosis by preventing caspase-3 cleavage of protein acinus.
• Understanding API-5's role in chemoresistant TNBC is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the therapeutic potential of targeting API-5 in chemoresistant TNBC.
• To determine if inhibiting API-5 can reverse chemoresistance and reduce tumor progression.
• To analyze the correlation between API-5 expression, angiogenesis, and hypoxic stress in TNBC.

Main Methods:

• Analysis of API-5 expression in 78 TNBC patient biopsies and patient-derived xenografts (XBC-R and XBC-S).
• In situ assessments of necrosis, cell proliferation, angiogenesis, and apoptosis in response to anti-API-5 peptide treatment.
• Transcriptomic analysis to identify gene expression patterns in XBC-R models.

Main Results:

• Higher API-5 expression in endothelial cells of chemoresistant TNBC patients correlated with increased micro-vessel density.
• API-5 expression was elevated in resistant XBC-R xenografts and linked to hypoxic stress.
• Anti-API-5 peptide treatment for 28 days significantly inhibited XBC-R xenografts through caspase-3 mediated apoptosis, reducing angiogenesis and increasing necrosis.

Conclusions:

• API-5 is overexpressed in chemoresistant TNBC, particularly in endothelial cells, and is associated with angiogenesis and hypoxia.
• Targeting API-5 with a peptide inhibitor effectively reversed chemoresistance and inhibited tumor growth in preclinical models.
• API-5 represents a promising therapeutic target for chemoresistant metastatic TNBC.