Optimizing therapeutic targets for breast cancer using boolean network models.

Studying gene regulatory networks associated with cancer provides valuable insights for therapeutic purposes, given that cancer is fundamentally a genetic disease. However, as the number of genes in the system increases, the complexity arising from the interconnections between network components grows exponentially. In this study, using Boolean logic to adjust the existing relationships between network components has facilitated simplifying the modeling process, enabling the generation of attractors that represent cell phenotypes based on breast cancer RNA-seq data. A key therapeutic objective is to guide cells, through targeted interventions, to transition from the current cancer attractor to a physiologically distinct attractor unrelated to cancer. To achieve this, we developed a computational method that identifies network nodes whose inhibition can facilitate the desired transition from one tumor attractor to another associated with apoptosis, leveraging transcriptomic data from cell lines. To validate the model, we utilized previously published in vitro experiments where the downregulation of specific proteins resulted in cell growth arrest and death of a breast cancer cell line. The method proposed in this manuscript combines diverse data sources, conducts structural network analysis, and incorporates relevant biological knowledge on apoptosis in cancer cells. This comprehensive approach aims to identify potential targets of significance for personalized medicine.

A Strategy Utilizing Protein-Protein Interaction Hubs for the Treatment of Cancer Diseases.

We describe a strategy for the development of a rational approach of neoplastic disease therapy based on the demonstration that scale-free networks are susceptible to specific attacks directed against its connective hubs. This strategy involves the (i) selection of up-regulated hubs of connectivity in the tumors interactome, (ii) drug repurposing of these hubs, (iii) RNA silencing of non-druggable hubs, (iv) in vitro hub validation, (v) tumor-on-a-chip, (vi) in vivo validation, and (vii) clinical trial. Hubs are protein targets that are assessed as targets for rational therapy of cancer in the context of personalized oncology. We confirmed the existence of a negative correlation between malignant cell aggressivity and the target number needed for specific drugs or RNA interference (RNAi) to maximize the benefit to the patient's overall survival. Interestingly, we found that some additional proteins not generally targeted by drug treatments might justify the addition of inhibitors designed against them in order to improve therapeutic outcomes. However, many proteins are not druggable, or the available pharmacopeia for these targets is limited, which justifies a therapy based on encapsulated RNAi.

Data-Driven Modeling of Breast Cancer Tumors Using Boolean Networks.

Cancer is a genomic disease involving various intertwined pathways with complex cross-communication links. Conceptually, this complex interconnected system forms a network, which allows one to model the dynamic behavior of the elements that characterize it to describe the entire system's development in its various evolutionary stages of carcinogenesis. Knowing the activation or inhibition status of the genes that make up the network during its temporal evolution is necessary for the rational intervention on the critical factors for controlling the system's dynamic evolution. In this report, we proposed a methodology for building data-driven boolean networks that model breast cancer tumors. We defined the network components and topology based on gene expression data from RNA-seq of breast cancer cell lines. We used a Boolean logic formalism to describe the network dynamics. The combination of single-cell RNA-seq and interactome data enabled us to study the dynamics of malignant subnetworks of up-regulated genes. First, we used the same Boolean function construction scheme for each network node, based on canalyzing functions. Using single-cell breast cancer datasets from The Cancer Genome Atlas, we applied a binarization algorithm. The binarized version of scRNA-seq data allowed identifying attractors specific to patients and critical genes related to each breast cancer subtype. The model proposed in this report may serve as a basis for a methodology to detect critical genes involved in malignant attractor stability, whose inhibition could have potential applications in cancer theranostics.