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for heterogeneous bioinformatics software components Although computer programs and database resources for bioinformatics applications are becoming more widely available, these resources are unstandardized and frequently incompatible. The problem of integrating heterogeneous software is of immense importance to the field, especially because a rapid pace of change and a general scarcity of development resources discourage re-engineering and compel developers to find ways to use legacy resources. In this paper, we describe an approach to the problem of integration of heterogeneous bioinformatics resources that relies on a generalized software platform, written in the Java TM language, that we call ISYS TM. The ISYS platform employs techniques for interoperation among loosely coupled components, such as brokered service exchange and mediated event exchange, that are increasingly common in software engineering but still not used widely in bioinformatics. In addition, it further promotes loose coupling of independent components through a flexible, semistructured data model that supports run-time association of attributes with objects, and allows different components to maintain different “views ” of the same object. We describe our general approach, the architecture of the system, the mechanics of event and service exchange, and the implementation of the data model. The platform is not restricted in its utility to bioinformatics, and could be useful for any rapidly changing field in which the integration of heterogeneous legacy components is important. The field of biology is becoming increasingly dependent on computer software. Molecular and cellular biologists, geneticists, and biochemists rely on analysis programs, modeling tools, databases, and visualization software to accomplish their everyda

VAV3 mediates resistance to breast cancer endocrine therapy

Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process. Methods: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA–mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression. Results: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10−4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy. Conclusions: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.This work was supported by grants from the Eugenio Rodríguez Pascual Foundation (2012, to MAP), the Government of Catalonia (2009-SGR283, to AV and MAP), the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (R01 DK015556, to JAK), the Red Cooperative Research Thematic Network on Cancer (RTICC) (12/0036/0002 to XRB and 12/0036/0008 to XRB and MAP) and the Spanish Ministry of Health, Fund for Health Research–Institute of Health Carlos III (11/00951 to AU and 12/01528 to MAP