Deciphering Breast Cancer Metastasis Cascade: A Systems Biology Approach Integrating Transcriptome and Interactome Insights for Target Discovery.

Abstract

Breast cancer is the lead cause of cancer-related deaths among women globally. Breast cancer metastasis is a complex and still inadequately understood process and a key dimension of mortality attendant to breast cancer. This study reports dysregulated genes across metastatic stages and tissues, shedding light on their molecular interplay in disease pathogenesis and new possibilities for drug discovery. Comprehensive analyses of gene expression data from primary breast tumor, circulating tumor cells, and distant metastatic sites in the brain, lung, liver, and bone were conducted. Genes dysregulated across multiple stages and tissues were identified as metastatic cascade genes, and are further classified based on functional associations with metastasis-related mechanisms. Their interactions with HUB genes in interactome networks were scrutinized, followed by pathway enrichment analysis. Validation for their potential as targets included assessments for survival, druggability, prognostic marker status, secretome annotation, protein expression, and cell type marker association. Results displayed critical genes in the metastatic cascade and those specific to metastatic sites, revealing the involvement of the collagen degradation and assembly of collagen fibrils and other multimeric structure pathways in driving metastasis. Notably, pivotal cascade genes FABP4, CXCL12, APOD, and IGF1 emerged with high metastatic potential, linked to significant druggability and survival scores, establishing them as potential molecular targets. The significance of this research lies in its potential to uncover novel biomarkers for early detection, therapeutic targets, and a deeper understanding of the molecular mechanisms underpinning the metastatic cascade in breast cancer, and with an eye to precision/personalized medicine.