Multi-Level Profiling of MAPK-Associated Genes and MicroRNAs Uncovers Regulatory Networks in Breast Cancer Subtypes

Area of Science:

• Oncology and Molecular Biology
• Investigates the molecular underpinnings of breast cancer heterogeneity.
• Focuses on signaling pathways and gene regulation in cancer progression.

Background:

• Breast cancer (BC) is a heterogeneous disease with diverse molecular drivers.
• The mitogen-activated protein kinase (MAPK) pathway is crucial for BC progression.
• MicroRNAs (miRNAs) are recognized regulators of MAPK-associated genes, but their role across BC subtypes is unclear.

Purpose of the Study:

• To comprehensively analyze the integrated role of MAPK-associated genes and miRNAs across distinct BC subtypes.
• To identify subtype-specific molecular alterations and potential therapeutic targets.
• To elucidate the interplay between gene expression, miRNA regulation, and protein interactions in BC.

Main Methods:

• Analysis of mRNA and miRNA expression in 405 BC patients across five subtypes (LumA, LumB HER2-, LumB HER2+, HER2+, TNBC).
• Utilized Affymetrix microarrays, RT-qPCR, ELISA, and bioinformatics tools (miRDB, STRING).
• Correlated gene and protein expression levels with miRNA profiles.

Main Results:

• Significant downregulation of MAP3K1, MAP2K4, and TP53, and upregulation of PPM1D, LMTK3, and TGFB1 observed across BC subtypes, particularly in TNBC.
• Concordant protein-level alterations confirmed gene expression changes.
• Dysregulated miRNAs (e.g., miR-21-3p, miR-205-3p) showed inverse expression to predicted targets.
• TP53 identified as a central hub connecting MAPK signaling to stress and apoptosis pathways.

Conclusions:

• Integrated transcriptomic and miRNA profiling highlights subtype-specific dysregulation of MAPK pathway components in BC.
• TNBC exhibits the most pronounced molecular alterations, suggesting unique therapeutic vulnerabilities.
• Findings provide a foundation for developing personalized therapeutic strategies targeting specific BC subtypes.