Berry-derived gold nanoparticles induce integrated ROS-mediated apoptosis, immune modulation, and transcriptomic...

Area of Science:

• Oncology
• Nanotechnology
• Molecular Biology

Background:

• Comprehensive characterization of breast cancer models is crucial for understanding disease mechanisms and developing effective therapies.
• Triple-negative breast cancer (4T1 cell line) presents unique challenges due to its aggressive nature and limited treatment options.
• Berry-derived polyphenols show therapeutic potential but suffer from poor bioavailability and stability, necessitating advanced delivery systems.

Purpose of the Study:

• To conduct a comprehensive molecular and phenotypic characterization of 4T1 triple-negative breast cancer cells.
• To investigate the integration of genomic vulnerabilities and mutational profiling with treatment-induced responses.
• To evaluate the efficacy of nanoencapsulated berry-derived polyphenols (AuNPs) in modulating cancer cell signaling and inducing apoptosis.

Main Methods:

• Whole-genome and transcriptome sequencing (Illumina NovaSeq X, NextSeq) and proteomic analysis of 4T1 cells.
• Physicochemical characterization of nanoencapsulated polyphenols using TEM, FTIR, and UPLC/MS-QQQ.
• Functional consequence analysis of identified mutations using AlphaFold and gene set enrichment analysis (GSEA).
• Immunohistochemical, immunofluorescent, and flow cytometric analyses to assess cellular responses to nanoparticle treatment.

Main Results:

• Identified significant mutations in breast cancer-related tumor suppressor genes (TP53, BRCA2, BARD1, CDH1, NF1, CHEK2) within conserved motifs.
• Detected ~5,700,000 single-nucleotide variations (SNVs) and 329,448 indels, providing extensive genomic data.
• GSEA revealed altered DNA repair, TGF-β signaling, cell adhesion, and MAPK pathways, suggesting modulation of apoptosis and immune evasion.
• Nanoencapsulated berry polyphenols induced caspase-dependent apoptosis via ROS, suppressed PI3K/AKT/mTOR signaling, and modulated JAK3/STAT3 pathways, leading to suppressed epithelial-to-mesenchymal transition (EMT) and metastatic potential.

Conclusions:

• Nanoencapsulated berry polyphenols represent a promising strategy for breast cancer therapy by targeting key signaling pathways.
• The study provides a deep molecular understanding of 4T1 cells and their response to novel therapeutic interventions.
• Functionalized gold nanoparticles (AuNPs) serve as effective delivery platforms for dietary phytochemicals, regulating apoptosis, autophagy, immune response, and metastasis in breast cancer.