Drug discovery by targeting the protein-protein interactions involved in autophagy

Autophagy is a cellular process in which proteins and organelles are engulfed in autophagosomal vesicles and transported to the lysosome/vacuole for degradation. Protein-protein interactions (PPIs) play a crucial role at many stages of autophagy, which present formidable but attainable targets for autophagy regulation. Moreover, selective regulation of PPIs tends to have a lower risk in causing undesired off-target effects in the context of a complicated biological network. Thus, small-molecule regulators, including peptides and peptidomimetics, targeting the critical PPIs involved in autophagy provide a new opportunity for innovative drug discovery. This article provides general background knowledge of the critical PPIs involved in autophagy and reviews a range of successful attempts on discovering regulators targeting those PPIs. Successful strategies and existing limitations in this field are also discussed.

Small molecules targeting protein-protein interactions for cancer therapy

Protein-protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.

Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design.@*METHODS@#Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database.@*RESULTS@#A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes.@*CONCLUSION@#Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.

Research progress of nicotinic receptor intracellular interaction proteins / 国际生物医学工程杂志

Nicotinic acetylcholine receptors(nAChRs) is one of the main receptor of acetylcholine in the body. It is an excitatory transmembrane cation channel. It is confirmed that nAChRs has important physiological functions in both the nervous system and non-nervous system, and is related to many diseases.nAChRs has also been confirmed to be related to many diseases, so its structure And functional research is very necessary. Therefore, it is necessary to study the structure and function of nAChRs. It is known that the intracellular loop of the nicotinic receptor protein plays a major role in regulating its intracellular metabolism and downstream signal transduction. However, the structure and function of this protein sequence are still unclear. In this paper, the current research status of nicotinic receptor intracellular interaction proteins were reviewed, aiming to further explore the structural and functional characteristics of nicotinic receptor intracellular loops through the information of their interaction proteins and interaction sites, and to provide ideas for clinical targeted therapy.

Reduced Distance Matrix to Verify the Similarity between Protein Structures

Abstract This paper focuses on developing a reduced distance matrix to improve the computational performance during the protein interactions clustering. This proposed matrix considers as centroids two alpha carbon atoms from a protein structure and stores the distances between these centroids and the other atoms from this same structure. Each row in this matrix represents a database record and each column is a distance value. Through this build matrix, clusters were performed using K-Means Clustering. The precision and performance of this presented technique were compared with aCSM, RID and another distance matrix methodology that considers the distances between all atoms from each protein structure. The results were satisfactory. The reduced distance matrix obtained a high precision and the best computational performance.

Dynamic conformational flexibility and molecular interactions of intrinsically disordered proteins

In order to improve crop plants in terms of their yield, drought resistance, pest resistance, nutritional value, etc.,modern agriculture has relied upon plant genetic engineering. Since the advent of recombinant DNA technology, several tools have been used for genetic transformations in plants such as Agrobacterium tumefaciens,virus-mediated gene transfer, direct gene transfer systems such as electroporation, particle gun, microinjectionand chemical methods. All these traditional methods lack specificity and the transgenes are integrated atrandom sites in the plant DNA. Recently novel techniques for gene targeting have evolved such as engineerednucleases such as Zinc Finger Nucleases, Transcription Activator like effector nucleases, Clustered regularinterspaced short palindromic repeats. Other advances include improvement in tools for delivery of geneediting components which include carrier proteins, and carbon nanotubes. The present review focuses on thelatest techniques for target specific gene delivery in plants, their expression and future directions in plantbiotechnology

Mining Polo-Box domain of Polo-like kinase 1 as a new therapeutic target for cancer / 生物工程学报

Polo-like kinase 1 (Plk1) is widely regarded as one of the most promising targets for cancer therapy due to its essential role in cell division and tumor cell survival. At present, most Plk1 inhibitors have been developed based on kinase domain, some of which are in clinical trial. However, inhibitors targeting kinase domain face off-target effect and drug resistance owing to the conserved nature and the frequent mutations in the ATP-binding pocket. In addition to a highly conserved kinase domain, Plk1 also contains a unique Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. Inhibitors targeting Plk1 PBD show stronger selectivity and less drug resistance for cancer therapy. Therefore, Plk1 PBD is an attractive target for the development of anti-cancer agents. In this review, we will summarize the up-to date drug discovery for targeting Plk1 PBD, including the molecular structure and cellular functions of Plk1 PBD. Small-molecule inhibitors targeting Plk1 PBD not only provide an opportunity to specifically inhibit Plk1 activity for cancer treatment, but also unveil novel biological basis regarding the molecular recognition of Plk1 and its substrates.

Comparative Analysis of Some Proteins Encoded by Genes Significantly Related to Diabetes

Aims: The study was performed with the aim of understanding the role of protein structures encoded by a few of those genes which show the most significant alterations in their expression under normal versus diabetic conditions. Study Design: The study involved identifying a few relevant genes and analysis of various components of their protein structures. Methodology: Nine genes were shortlisted based on the extensive search of available secondary data. The structures of proteins encoded by them were generated using standard online tools. Comparative models of each of them were also generated in reference to the gene PPARγ due to its high significance in both diabetes as well as obesity, one of its predominant contributing factors. Results: Our studies indicate that the protein structures have domains which can interact with each other as well as other signaling molecules and thereby contribute towards the transfer of information across the cells. Moreover, some of these proteins show significant overlap with the protein encoded by the gene PPARγ, indicating probable interactions between them. Conclusion: These preliminary observations are indicative of probable protein-protein interactions which may contribute towards disease pathology. Further studies on interactions between these domains of various proteins may throw light on this aspect. Since diabetes incidences are increasing exponentially across the world, further detailed analysis of the individual components of the protein structures may help in obtaining a better understanding of the molecular mechanisms that are involved in this disease. This study substantiates those findings which have reported the importance of genetics in diabetes.

Arrestins: structural disorder creates rich functionality

Arrestins are soluble relatively small 44-46 kDa proteins that specifically bind hundreds of active phosphorylated GPCRs and dozens of non-receptor partners. There are binding partners that demonstrate preference for each of the known arrestin conformations: free, receptor-bound, and microtubule-bound. Recent evidence suggests that conformational flexibility in every functional state is the defining characteristic of arrestins. Flexibility, or plasticity, of proteins is often described as structural disorder, in contrast to the fixed conformational order observed in high-resolution crystal structures. However, protein-protein interactions often involve highly flexible elements that can assume many distinct conformations upon binding to different partners. Existing evidence suggests that arrestins are no exception to this rule: their flexibility is necessary for functional versatility. The data on arrestins and many other multi-functional proteins indicate that in many cases, "order" might be artificially imposed by highly non-physiological crystallization conditions and/or crystal packing forces. In contrast, conformational flexibility (and its extreme case, intrinsic disorder) is a more natural state of proteins, representing true biological order that underlies their physiologically relevant functions.

TICA: Transcriptional Interaction and Coregulation Analyzer / 基因组蛋白质组与生物信息学报·英文版

Transcriptional regulation is critical to cellular processes of all organisms. Regulatory mechanisms often involve more than one transcription factor (TF) from different families, binding together and attaching to the DNA as a single complex. However, only a fraction of the regulatory partners of each TF is currently known. In this paper, we present the Transcriptional Interaction and Coregulation Analyzer (TICA), a novel methodology for predicting heterotypic physical interaction of TFs. TICA employs a data-driven approach to infer interaction phenomena from chromatin immunoprecipitation and sequencing (ChIP-seq) data. Its prediction rules are based on the distribution of minimal distance couples of paired binding sites belonging to different TFs which are located closest to each other in promoter regions. Notably, TICA uses only binding site information from input ChIP-seq experiments, bypassing the need to do motif calling on sequencing data. We present our method and test it on ENCODE ChIP-seq datasets, using three cell lines as reference including HepG2, GM12878, and K562. TICA positive predictions on ENCODE ChIP-seq data are strongly enriched when compared to protein complex (CORUM) and functional interaction (BioGRID) databases. We also compare TICA against both motif/ChIP-seq based methods for physical TF-TF interaction prediction and published literature. Based on our results, TICA offers significant specificity (average 0.902) while maintaining a good recall (average 0.284) with respect to CORUM, providing a novel technique for fast analysis of regulatory effect in cell lines. Furthermore, predictions by TICA are complementary to other methods for TF-TF interaction prediction (in particular, TACO and CENTDIST). Thus, combined application of these prediction tools results in much improved sensitivity in detecting TF-TF interactions compared to TICA alone (sensitivity of 0.526 when combining TICA with TACO and 0.585 when combining with CENTDIST) with little compromise in specificity (specificity 0.760 when combining with TACO and 0.643 with CENTDIST). TICA is publicly available at http://geco.deib.polimi.it/tica/.

Conformation-locked nucleation strategies ofα-helical peptides / 国际药学研究杂志

Protein-protein interactions(PPI)with large and shallow interfaces are generally undruggable targets. Many PPI in-volved in vital biological processes are mediated by helixes,therefore PPI can be easily targeted by helical epitope mimics. However, the application of peptide was limited by its conformational flexibility and low stability until the significant work was done by Arora ,et al who applied nucleation and crosslinking strategies to lock peptides in helical conformation. The conformation-locked strategies helps to improve peptide stability,cell permeability,and afterwards target intracellular PPI. At present,the conformation-locked strategies of peptides have achieved great development,and have become a hot spot in peptide research field. In this paper,the recent develop-ment,centering nucleation strategies,applications and bright prospects of helical conformation-locked peptides,are reviewed in order to provide theoretical basis for drug design based on PPI.

Identification of a novel target for cancer and anti-fibrotic therapy / 中国药理学与毒理学杂志

Gene transcription mechanisms are critical control points for cell function and differentiation as well as disease pathology. It has remained difficult to target gene transcription mechanisms with small molecule drugs due in part to the role of protein-protein interactions in transcription complexes. RhoA/C- GTPase regulation of the serum responsive transcription factor complex involving serum response factor (SRF) and myocardin-related transcription factor (MRTF) plays a key role in cancer and fibrotic mechanisms. In an attempt to disrupt this critical gene transcription mechanism, we undertook a high-throughput ″pathway screen″ using an SRE-Luciferase reporter which was activated by transient transfection of HEK293 cells with Ga13, an up- stream activator of RhoA and RhoC. The Rho/MRTF inhibitor tool compound CCG-1423 was identified in this screen. It and analogs such as CCG-203971 have been used extensively to disrupt myofibroblast activation and tissue fibrosis as well as melanoma cell migration and metastasis. In the present study, we have used immobilized compounds and mass spectroscopy to identify the molecular target of the CCG-203971 series of anti-fibrotic and anti-meta?static agents. It is a poorly studied intranuclear protein that participates in gene transcription regulation by NF-κB and MRTF/SRF mechanisms. This dual mechanism rationalizes the strong efficacy of CCG-203971 and related compounds as anti-fibrotic and anti-metastatic agents. The identification of a molecular target also greatly facilitates future compound development through structure- based drug discovery and target biology evaluation.

Dengue virus non-structural 1 protein interacts with heterogeneous nuclear ribonucleoprotein H in human monocytic cells

Objective: To study protein-protein interaction between heterogeneous nuclear ribonucleoprotein H (hnRNP H) and Dengue virus (DENV) proteins. Methods: DENV proteins were screened against the host hnRNP H protein, in order to identify the host-viral protein-protein interactions in DENV infected THP-1 cells by co-immunoprecipitation. The co-localization of the interacting proteins was further confirmed by immunofluorescence microscopy. Results: The host protein hnRNP H was found to interact with DENV non-structural 1 protein and help the virus to multiply in the cell. Conclusions: The non-structural 1 glycoprotein is a key modulator of host immune response and is also involved in viral replication. Therefore, disruption of this key interaction between hnRNP H and DENV non-structural 1 could be an important therapeutic strategy for management of DENV infection.

Dengue virus non-structural 1 protein interacts with heterogeneous nuclear ribonucleoprotein H in human monocytic cells

OBJECTIVE@#To study protein-protein interaction between heterogeneous nuclear ribonucleoprotein H (hnRNP H) and Dengue virus (DENV) proteins.@*METHODS@#DENV proteins were screened against the host hnRNP H protein, in order to identify the host-viral protein-protein interactions in DENV infected THP-1 cells by co-immunoprecipitation. The co-localization of the interacting proteins was further confirmed by immunofluorescence microscopy.@*RESULTS@#The host protein hnRNP H was found to interact with DENV non-structural 1 protein and help the virus to multiply in the cell.@*CONCLUSIONS@#The non-structural 1 glycoprotein is a key modulator of host immune response and is also involved in viral replication. Therefore, disruption of this key interaction between hnRNP H and DENV non-structural 1 could be an important therapeutic strategy for management of DENV infection.

Vias de transdução de sinal e polimorfismo de Toll-like Receptors na carcinogenese por HPV / Toll-like Receptors signaling pathway and polymorphism on the HPV carcinogenesis

Seres humanos dependem incessantemente de um sistema de reconhecimento efetivo contra infecções para sobreviver. Dentre as diversas proteínas que compõem a resposta imune inata estão os receptores do tipo Toll (TLR Toll-like Receptors), que possuem a função de reconhecer padrões moleculares associados a patógenos e dar início a uma resposta imune adequada. O carcinoma do colo uterino é uma das principais causas de morte de mulheres por câncer mundialmente, sendo o terceiro tipo de câncer mais comum entre mulheres. Este tipo de neoplasia é vinculada etiologicamente à infecção pelo Papilomavírus humano (HPV). Dentre as principais proteínas virais, E6 e E7 são responsáveis pela manipulação dos processos celulares para promover ciclo viral, sendo essenciais no processo de transformação celular. Nesse contexto, o objetivo deste trabalho foi investigar a importância da via de sinalização de TLRs sobre a infecção por HPV. O polimorfismo rs5743836, na região promotora de TLR9, capaz de alterar a expressão deste receptor, foi estudado quanto à influência sobre a história natural da infecção por HPV em uma coorte de mulheres brasileiras; nenhuma associação relevante foi encontrada, indicando que este polimorfismo não interfere significativamente na resposta à infecção e risco de desenvolvimento de lesões no colo do útero causadas por HPV. Proteínas componentes da via de TLRs demonstraram serem alvos de interação com E6 de HPV16; dentre elas, o notável adaptador MyD88 e IKKε, enzima ativadora de importantes transfatores do sistema imune. Estas interações foram aqui estudadas. A interação de E6 com MyD88 resultou em estabilização da proteína viral, o que parece não depender do sítio LxxLL presente em MyD88, como ocorre com outros parceiros moleculares de E6. O sítio de interação de E6 com IKKε coincide com a região onde se localiza o sítio catalítico desta enzima, sugerindo a ação de E6 na ativação de proteínas alvo de IKKε. Esta interação foi observada em queratinócitos, células alvo das infecções por HPV. A produção de citocinas foi afetada por E6 de HPV16, resultando num aumento da quantidade de IL-8 e IL-6; a indução desta citocina poderia ser explicada pela ativação de IKKε. Estes resultados apontam para a capacidade do HPV16 de interferir com o sistema imune, contribuindo para o processo de carcinogênese

Humans constantly rely on an effective recognition system against infections in order to survive. Among various proteins that compose the innate immune response, Toll-like Receptors (TLRs) have the role to recognize pathogen associated molecular patterns and initiate a proper immune response. The cervical cancer is one of the main causes of women death worldwide, being the third most common cancer type among women. This type of neoplasia is etiologically associated with the Human papillomavirus (HPV) infection. E6 and E7, two main viral proteins, are responsible for manipulating the cellular processes to promote the virus' life-cycle, being essential to the cellular transformation process. In the context, the objective of this work was to investigate the relevance of the TLR signaling pathway on the HPV infection. The rs5743836 polymorphism, in the TLR9 promoter region, capable of altering this receptor's expression, was studied regarding its influence on the natural history of HPV infection in a Brazilian women cohort; no relevant association was found, indicating that this polymorphism does not interfere significantly in the infection response and risk of developing cervix lesions caused by HPV. Component proteins of TLR pathway were shown to be interaction targets of HPV16 E6; among them, the notable adaptor MyD88 and IKKε, enzyme that activates important immune system transfactors. These interactions were studied in this work. The interaction of E6 with MyD88 resulted in the stabilization of the viral protein, which seems independent of the LxxLL site present on MyD88, as in other E6 molecular partners. The interaction site on IKK with E6 matches with the region containing the enzyme's catalytic site, suggesting an influence of E6 in the activation of IKKε target proteins. This interaction was observed in keratinocytes, natural targets of HPV infections. The cytokines production was altered by HPV16 E6, resulting in an increase of IL-8 and IL-6 concentration; the induction of the latter could be explained by the activation of IKKε. These results point to the ability of HPV16 of interfering with the immune system, contributing to the carcinogenesis process

La modificación covalente de proteínas. Un nivel cualitativamente superior de la información molecular / Covalent Modifications of Proteins. A qualitative higher level of molecular information

Introducción: La información molecular es una propiedad principal de las biomacromoléculas, especialmente proteínas y ácidos nucleicos, que permite la realización de funciones con un alto grado de especificidad. Ella deriva de la variedad en los componentes de las macromoléculas. Objetivo: Demostrar que la modificación covalente de proteínas constituye un nivel nuevo y superior de información molecular. Método: Se analizaron artículos de los últimos 5 años, publicados en revistas nacionales y de circulación internacional, disponibles en las bases de datos HINARI, PubMed y Perii y localizados mediante el sitio www.infomed.sld.cu. Desarrollo: Se exponen los mecanismos y características principales del proceso y posteriormente algunos de los efectos principales de la modificación covalente sobre las funciones y propiedades de las proteínas. Conclusiones: La modificación covalente es un mecanismo que amplía el campo de acción de las proteínas permitiendo un rápido cambio en sus propiedades funcionales y, por lo tanto, constituye un nivel nuevo y cualitativamente superior de información molecular.

Introduction: Molecular information is an essential property of biomacromolecules, especially proteins and nucleic acids. This property allows carrying out specific functions. It derives from variability of macromolecules components. Objetive: To prove that covalent modification of proteins represents a new and higher level of molecular information. Method: Papers published during the last five years in national and international journals were analyzed. These articles are available in HINARI, PubMed, and Perii databases and were localized through www.infomed.sld.cu. Main text: First, the mechanism and features of covalent modifications of protein are presented. Next, the principal effects on protein functions and properties are analyzed. Conclusions: We conclude that covalent modification of proteins represents a new and higher level of molecular information.

Reviewing host proteins of Rhabdoviridae: Possible leads for lesser studied viruses.

Rhabdoviridae, characterized by bullet-shaped viruses, is known for its diverse host range, which includes plants, arthropods, fishes and humans. Understanding the viral–host interactions of this family can prove beneficial in developing effective therapeutic strategies. The host proteins interacting with animal rhabdoviruses have been reviewed in this report. Several important host proteins commonly interacting with animal rhabdoviruses are being reported, some of which, interestingly, have molecular features, which can serve as potential antiviral targets. This review not only provides the generalized importance of the functions of animal rhabdovirus-associated host proteins for the first time but also compares them among the two most studied viruses, i.e. Rabies virus (RV) and Vesicular Stomatitis virus (VSV). The comparative data can be used for studying emerging viruses such as Chandipura virus (CHPV) and the lesser studied viruses such as Piry virus (PIRYV) and Isfahan virus (ISFV) of the Rhabdoviridae family.

Water-mediated ionic interactions in protein structures.

It is well known that water molecules play an indispensable role in the structure and function of biological macromolecules. The water-mediated ionic interactions between the charged residues provide stability and plasticity and in turn address the function of the protein structures. Thus, this study specifically addresses the number of possible water-mediated ionic interactions, their occurrence, distribution and nature found in 90% non-redundant protein chains. Further, it provides a statistical report of different charged residue pairs that are mediated by surface or buried water molecules to form the interactions. Also, it discusses its contributions in stabilizing various secondary structural elements of the protein. Thus, the present study shows the ubiquitous nature of the interactions that imparts plasticity and flexibility to a protein molecule.

Heparan sulfate proteoglycans: structure, protein interactions and cell signaling

Heparan sulfate proteoglycans are ubiquitously found at the cell surface and extracellular matrix in all the animal species. This review will focus on the structural characteristics of the heparan sulfate proteoglycans related to protein interactions leading to cell signaling. The heparan sulfate chains due to their vast structural diversity are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, morphogens, extracellular matrix components, enzymes, among others. There is a specificity directing the interactions of heparan sulfates and target proteins, regarding both the fine structure of the polysaccharide chain as well precise protein motifs. Heparan sulfates play a role in cellular signaling either as receptor or co-receptor for different ligands, and the activation of downstream pathways is related to phosphorylation of different cytosolic proteins either directly or involving cytoskeleton interactions leading to gene regulation. The role of the heparan sulfate proteoglycans in cellular signaling and endocytic uptake pathways is also discussed.

Proteoglicanos de heparam sulfato são encontrados tanto superfície celular quanto na matriz extracelular em todas as espécies animais. Esta revisão tem enfoque nas características estruturais dos proteoglicanos de heparam sulfato e nas interações destes proteoglicanos com proteínas que levam à sinalização celular. As cadeias de heparam sulfato, devido a sua variedade estrutural, são capazes de se ligar e interagir com ampla gama de proteínas, como fatores de crescimento, quimiocinas, morfógenos, componentes da matriz extracelular, enzimas, entreoutros. Existe uma especificidade estrutural que direciona as interações dos heparam sulfatos e proteínas alvo. Esta especificidade está relacionada com a estrutura da cadeia do polissacarídeo e os motivos conservados da cadeia polipeptídica das proteínas envolvidas nesta interação. Os heparam sulfatos possuem papel na sinalização celular como receptores ou coreceptores para diferentes ligantes. Esta ligação dispara vias de sinalização celular levam à fosforilação de diversas proteínas citosólicas ou com ou sem interações diretas com o citoesqueleto, culminando na regulação gênica. O papel dos proteoglicanos de heparam sulfato na sinalização celular e vias de captação endocítica também são discutidas nesta revisão.

Microarray Data Analysis of Perturbed Pathways in Breast Cancer Tissues

Due to the polygenic nature of cancer, it is believed that breast cancer is caused by the perturbation of multiple genes and their complex interactions, which contribute to the wide aspects of disease phenotypes. A systems biology approach for the identification of subnetworks of interconnected genes as functional modules is required to understand the complex nature of diseases such as breast cancer. In this study, we apply a 3-step strategy for the interpretation of microarray data, focusing on identifying significantly perturbed metabolic pathways rather than analyzing a large amount of overexpressed and underexpressed individual genes. The selected pathways are considered to be dysregulated functional modules that putatively contribute to the progression of disease. The subnetwork of protein-protein interactions for these dysregulated pathways are constructed for further detailed analysis. We evaluated the method by analyzing microarray datasets of breast cancer tissues; i.e., normal and invasive breast cancer tissues. Using the strategy of microarray analysis, we selected several significantly perturbed pathways that are implicated in the regulation of progression of breast cancers, including the extracellular matrix-receptor interaction pathway and the focal adhesion pathway. Moreover, these selected pathways include several known breast cancer-related genes. It is concluded from this study that the present strategy is capable of selecting interesting perturbed pathways that putatively play a role in the progression of breast cancer and provides an improved interpretability of networks of protein-protein interactions.