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Identifying intracellular signaling modules and exploring pathways associated with breast cancer recurrence.

ABSTRACT: Exploring complex modularization of intracellular signal transduction pathways is critical to understanding aberrant cellular responses during disease development and drug treatment. IMPALA (Inferred Modularization of PAthway LAndscapes) integrates information from high throughput gene expression experiments and genome-scale knowledge databases to identify aberrant pathway modules, thereby providing a powerful sampling strategy to reconstruct and explore pathway landscapes. Here IMPALA identifies pathway modules associated with breast cancer recurrence and Tamoxifen resistance. Focusing on estrogen-receptor (ER) signaling, IMPALA identifies alternative pathways from gene expression data of Tamoxifen treated ER positive breast cancer patient samples. These pathways were often interconnected through cytoplasmic genes such as IRS1/2, JAK1, YWHAZ, CSNK2A1, MAPK1 and HSP90AA1 and significantly enriched with ErbB, MAPK, and JAK-STAT signaling components. Characterization of the pathway landscape revealed key modules associated with ER signaling and with cell cycle and apoptosis signaling. We validated IMPALA-identified pathway modules using data from four different breast cancer cell lines including sensitive and resistant models to Tamoxifen. Results showed that a majority of genes in cell cycle/apoptosis modules that were up-regulated in breast cancer patients with short survivals (

SUBMITTER: Chen X

PROVIDER: S-EPMC7801429 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Identifying intracellular signaling modules and exploring pathways associated with breast cancer recurrence.

Chen Xi X Gu Jinghua J Neuwald Andrew F AF Hilakivi-Clarke Leena L Clarke Robert R Xuan Jianhua J

Scientific reports 20210111 1

Exploring complex modularization of intracellular signal transduction pathways is critical to understanding aberrant cellular responses during disease development and drug treatment. IMPALA (Inferred Modularization of PAthway LAndscapes) integrates information from high throughput gene expression experiments and genome-scale knowledge databases to identify aberrant pathway modules, thereby providing a powerful sampling strategy to reconstruct and explore pathway landscapes. Here IMPALA identifie ...[more]

PMID: 33432018

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Project description:MotivationProtein phosphorylation is a ubiquitous mechanism of post-translational modification that plays a central role in cellular signaling. Phosphorylation is particularly important in the context of cancer, as downregulation of tumor suppressors and upregulation of oncogenes by the dysregulation of associated kinase and phosphatase networks are shown to have key roles in tumor growth and progression. Despite recent advances that enable large-scale monitoring of protein phosphorylation, these data are not fully incorporated into such computational tasks as phenotyping and subtyping of cancers.ResultsWe develop a network-based algorithm, CoPPNet, to enable unsupervised subtyping of cancers using phosphorylation data. For this purpose, we integrate prior knowledge on evolutionary, structural and functional association of phosphosites, kinase-substrate associations and protein-protein interactions with the correlation of phosphorylation of phosphosites across different tumor samples (a.k.a co-phosphorylation) to construct a context-specific-weighted network of phosphosites. We then mine these networks to identify subnetworks with correlated phosphorylation patterns. We apply the proposed framework to two mass-spectrometry-based phosphorylation datasets for breast cancer (BC), and observe that (i) the phosphorylation pattern of the identified subnetworks are highly correlated with clinically identified subtypes, and (ii) the identified subnetworks are highly reproducible across datasets that are derived from different studies. Our results show that integration of quantitative phosphorylation data with network frameworks can provide mechanistic insights into the differences between the signaling mechanisms that drive BC subtypes. Furthermore, the reproducibility of the identified subnetworks suggests that phosphorylation can provide robust classification of disease response and markers.Availability and implementationCoPPNet is available at http://compbio.case.edu/coppnet/.Supplementary informationSupplementary data are available at Bioinformatics online.

Project description:BackgroundResistance to chemotherapy severely limits the effectiveness of chemotherapy drugs in treating cancer. Still, the mechanisms and critical pathways that contribute to chemotherapy resistance are relatively unknown. This study elucidates the chemoresistance-associated pathways retrieved from the integrated biological interaction networks and identifies signature genes relevant for chemotherapy resistance.MethodsAn integrated network was constructed by collecting multiple metabolic interactions from public databases and the k-shortest path algorithm was implemented to identify chemoresistant related pathways. The identified pathways were then scored using differential expression values from microarray data in chemosensitive and chemoresistant ovarian and lung cancers. Finally, another pathway database, Reactome, was used to evaluate the significance of genes within each filtered pathway based on topological characteristics.ResultsBy this method, we discovered pathways specific to chemoresistance. Many of these pathways were consistent with or supported by known involvement in chemotherapy. Experimental results also indicated that integration of pathway structure information with gene differential expression analysis can identify dissimilar modes of gene reactions between chemosensitivity and chemoresistance. Several identified pathways can increase the development of chemotherapeutic resistance and the predicted signature genes are involved in drug resistant during chemotherapy. In particular, we observed that some genes were key factors for joining two or more metabolic pathways and passing down signals, which may be potential key targets for treatment.ConclusionsThis study is expected to identify targets for chemoresistant issues and highlights the interconnectivity of chemoresistant mechanisms. The experimental results not only offer insights into the mode of biological action of drug resistance but also provide information on potential key targets (new biological hypothesis) for further drug-development efforts.

Dataset Information

Identifying intracellular signaling modules and exploring pathways associated with breast cancer recurrence.

Publications

Identifying intracellular signaling modules and exploring pathways associated with breast cancer recurrence.

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