Time to focus again on matrix metalloproteinases? Results of complex network analysis involving the pathophysiology of HER2-positive breast cancer.

Abstract

Breast cancer is the most common cancer in women worldwide, with significant advances in understanding its multifactorial nature in recent years. The complex structure of molecular and cellular interactions in cancer pathophysiology presents challenges for developing effective treatments. One theoretical model used to study these interactions is the Graph model or Complex Networks, which uses mathematical methods to create graphical figures by connecting vertices (factors) through edges (interactions). This study uses the graph model to determine the complex interactions within the tumour microenvironment of HER2-positive breast cancer. Through a narrative review, 37 factors involved in the pathophysiology of HER2-positive breast cancer were identified and incorporated into a complex network design, starting with the HER2 vertex. The impact of each vertex was determined by calculating the relative error, and a knockout (KO) analysis of vertices was performed to identify their influences within the network. The Wilcoxon test was used to analyze the statistical significance of each KO. Significant alterations in the network structure were observed with the KOs of matrix metalloproteinases (MMPMMP2, MMP9, cyclin-dependent kinases 4/6, TWIST, vascular endothelial growth factor and transforming growth factor-beta. Notably, the KOs of (MMPs) MMP2 and MMP9 significantly impacted the network structure and downregulated the HER2 vertex. This raises questions about the potential applicability of targeting MMPs, including the option of HER2-directed antibody-drug conjugates. Could a metalloprotease inhibitor be a good choice for conjugation? Despite the theoretical nature of this model, the results suggest potential avenues for therapeutic intervention.