title: Differential network analysis applied to preoperative breast cancer chemotherapy response.
abstract: In silico approaches are increasingly considered to improve breast cancer treatment. One of these treatments, neoadjuvant TFAC chemotherapy, is used in cases where application of preoperative systemic therapy is indicated. Estimating response to treatment allows or improves clinical decision-making and this, in turn, may be based on a good understanding of the underlying molecular mechanisms. Ever increasing amounts of high throughput data become available for integration into functional networks. In this study, we applied our software tool ExprEssence to identify specific mechanisms relevant for TFAC therapy response, from a gene/protein interaction network. We contrasted the resulting active subnetwork to the subnetworks of two other such methods, OptDis and KeyPathwayMiner. We could show that the ExprEssence subnetwork is more related to the mechanistic functional principles of TFAC therapy than the subnetworks of the other two methods despite the simplicity of ExprEssence. We were able to validate our method by recovering known mechanisms and as an application example of our method, we identified a mechanism that may further explain the synergism between paclitaxel and doxorubicin in TFAC treatment: Paclitaxel may attenuate MELK gene expression, resulting in lower levels of its target MYBL2, already associated with doxorubicin synergism in hepatocellular carcinoma cell lines. We tested our hypothesis in three breast cancer cell lines, confirming it in part. In particular, the predicted effect on MYBL2 could be validated, and a synergistic effect of paclitaxel and doxorubicin could be demonstrated in the breast cancer cell lines SKBR3 and MCF-7.
authors.affiliation: Institute for Biostatistics and Informatics in Medicine and Ageing Research, University of Rostock Medical School, Rostock, Germany ; Department of Mathematics and Informatics, University of Greifswald, Greifswald, Germany ; Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Warsow
authors.affiliation: Institute for Biostatistics and Informatics in Medicine and Ageing Research, University of Rostock Medical School, Rostock, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Struckmann
authors.affiliation: Department of Biomedical Sciences, School of Human Sciences, University of Osnabrueck, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Kerkhoff
authors.affiliation: Department of Obstetrics and Gynecology, University of Rostock Medical School, Germany.
authors.forename: Toralf
authors.initials: T
authors.lastname: Reimer
authors.affiliation: Department of Cell Biology, University of Rostock Medical School, Rostock, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Engel
authors.affiliation: Institute for Biostatistics and Informatics in Medicine and Ageing Research, University of Rostock Medical School, Rostock, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Fuellen
mesh_terms: D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks; D006801:Humans; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012984:Software; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D054316:Biomarkers, Pharmacological; D018797:Cell Cycle Proteins; C064352:MYBL2 protein, human; D015534:Trans-Activators; D004317:Doxorubicin; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel