Abstract
Most cancer studies employ adjacent normal tissues to tumors (ANTs) as controls, which are not completely normal and represent a pre-cancerous state. However, the regulatory landscape of ANTs compared to tumor and non-tumor-bearing normal tissues is largely unexplored. Among cancers, breast cancer is the most commonly diagnosed cancer and a leading cause of death in women worldwide, with a lack of sufficient treatment regimens for various reasons. Hence, we aimed to gain deeper insights into normal, pre-cancerous, and cancerous regulatory systems of breast tissues towards identifying ANT and subtype-specific candidate genes. For this, we constructed and analyzed eight gene regulatory networks (GRNs), including five subtypes (viz., Basal, Her2, Luminal A, Luminal B, and Normal-Like), one ANT, and two normal tissue networks. Whereas several topological properties of these GRNs enabled us to identify tumor-related features of ANT, escape velocity centrality (EVC+) identified 24 functionally significant common genes, including well-known genes such as E2F1, FOXA1, JUN, BRCA1, GATA3, ERBB2, and ERBB3 across all six tissues including subtypes and ANT. Similarly, the EVC+ also helped us to identify tissue-specific key genes (Basal: 18, Her2: 6, Luminal A: 5, Luminal B: 5, Normal-Like: 2, and ANT: 7). Additionally, differentially correlated switching gene pairs along with functional, pathway, and disease annotations highlighted the cancer-associated role of these genes. In a nutshell, the present study revealed ANT and subtype-specific regulatory features and key candidate genes, which can be explored further using in vitro and in vivo experiments for better and effective disease management at an early stage.
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