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Pfefferle A.D.,University of North Carolina at Chapel Hill | Herschkowitz J.I.,University at Albany | Usary J.,University of North Carolina at Chapel Hill | Harrell J.C.,University of North Carolina at Chapel Hill | And 9 more authors.
Genome Biology | Year: 2013

Background: Human breast cancer is a heterogeneous disease consisting of multiple molecular subtypes. Genetically engineered mouse models are a useful resource for studying mammary cancers in vivo under genetically controlled and immune competent conditions. Identifying murine models with conserved human tumor features will facilitate etiology determinations, highlight the effects of mutations on pathway activation, and should improve preclinical drug testing.Results: Transcriptomic profiles of 27 murine models of mammary carcinoma and normal mammary tissue were determined using gene expression microarrays. Hierarchical clustering analysis identified 17 distinct murine subtypes. Cross-species analyses using three independent human breast cancer datasets identified eight murine classes that resemble specific human breast cancer subtypes. Multiple models were associated with human basal-like tumors including TgC3(1)-Tag, TgWAP-Myc and Trp53-/-. Interestingly, the TgWAPCre-Etv6 model mimicked the HER2-enriched subtype, a group of human tumors without a murine counterpart in previous comparative studies. Gene signature analysis identified hundreds of commonly expressed pathway signatures between linked mouse and human subtypes, highlighting potentially common genetic drivers of tumorigenesis.Conclusions: This study of murine models of breast carcinoma encompasses the largest comprehensive genomic dataset to date to identify human-to-mouse disease subtype counterparts. Our approach illustrates the value of comparisons between species to identify murine models that faithfully mimic the human condition and indicates that multiple genetically engineered mouse models are needed to represent the diversity of human breast cancers. The reported trans-species associations should guide model selection during preclinical study design to ensure appropriate representatives of human disease subtypes are used. © 2013 Pfefferle et al.; licensee BioMed Central Ltd. Source

Rossant J.,Peter Gilgan Center for Research and Learning | Rossant J.,University of Toronto
Development (Cambridge) | Year: 2015

Lessons learned from conserved vertebrate developmental pathways have catalyzed rapid advances in pluripotent stem cell differentiation towards therapeutically relevant cell types. The most highly conserved phases of development are associated with the early patterning of the body plan-the so-called phylotypic stage. Both prior to and after this stage there is much more divergence across species. Developmental differences between human and mouse at the blastocyst and early post-implantation stages might help explain the differences among the different stem cell lines derived from these embryos. A better understanding of these early stages of human development will aid our ability to generate and manipulate human stem cells and their derivatives. © 2015. Published by The Company of Biologists Ltd. Source

Raja M.,Max Planck Institute of Molecular Physiology | Raja M.,Peter Gilgan Center for Research and Learning | Kinne R.K.H.,Max Planck Institute of Molecular Physiology
Biochimie | Year: 2015

The sodium glucose cotransporter SGLT1 expressed mainly in the intestine and kidney has been explored extensively for understanding the mechanism of sugar cotransport and its inhibition by a classical competitive inhibitor, phlorizin (Pz). It has been shown that inhibition of SGLT1 by Pz involves its interaction followed by major conformational changes in the Pz binding domain (PBD) in C-terminal loop 13. However, the mechanism of Pz inhibition and its interaction with other members of SGLT is not known. In this hypothesis, we performed molecular modeling of SGLT1-loop 13 with Pz and carried out primary sequence analyses and secondary structure predictions to determine qualitatively similar PBDs in C-termini of human SGLT2-4, except for vSGLT, which contains an unstructured short C-terminus. The ranking of predictions of Pz interaction strongly agrees with the following ranking of previously reported Pz inhibition: SGLT2>SGLT1>SGLT4>SGLT3>>vSGLT. In addition, the sugar binding residues were found to be quite conserved among all SGLT members investigated here. Based on these preliminary analyses, we propose that other Pz-sensitive SGLTs are also inhibited via mechanism similar to SGLT1 where an aglucone of Pz, phloretin, interacts with PBD and glucoside moiety with sugar binding residues. Our hypothesis sets the stage for future analyses on investigation of Pz interaction with SGLT family and further suggests that Pz modeling may be explored to design novel inhibitors targeting several SGLT members. © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved. Source

Gordon J.A.R.,University of Vermont | Lisle J.W.,University of Vermont | Alman B.A.,Peter Gilgan Center for Research and Learning | Alman B.A.,Duke University | Lian J.B.,University of Vermont
Journal of Cellular Physiology | Year: 2014

Skeletal metastasis is a serious complication of many primary cancers. A common feature of tumor cells that metastasize to the bone marrow microenvironment is that they initiate a cascade of events, recruiting and presumably/potentially altering the phenotype of bone marrow mesenchymal stromal cells (MSC) to produce an environment that allows for tumor growth and in some cases, drug-resistant dormancy of latent cancer cells. Consequently the MSC population can contribute to metastatic disease through several distinct mechanisms by differentiating into cancer-associated fibroblasts (CAFs). Understanding the expression and epigenetic changes that occur as normal MSCs become associated with metastatic tumors would reveal possible therapeutic targets for treating skeletal metastasis. © 2014 Wiley Periodicals, Inc. Source

Ardelean D.S.,The Hospital for Sick Children | Letarte M.,Peter Gilgan Center for Research and Learning | Letarte M.,University of Toronto
Frontiers in Genetics | Year: 2015

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplastic disorder, characterized by recurrent nosebleeds (epistaxis), multiple telangiectases and arteriovenous malformations (AVMs) in major organs. Mutations in Endoglin (ENG or CD105) and Activin receptor-like kinase 1 (ACVRL1 or ALK1) genes of the TGF-ß superfamily receptors are responsible for HHT1 and HHT2 respectively and account for the majority of HHT cases. Haploinsufficiency in ENG and ALK1 is recognized at the underlying cause of HHT. However, the mechanisms responsible for the predisposition to and generation of AVMs, the hallmark of this disease, are poorly understood. Recent data suggest that dysregulated angiogenesis contributes to the pathogenesis of HHT and that the vascular endothelial growth factor, VEGF, may be implicated in this disease, by modulating the angiogenic-angiostatic balance in the affected tissues. Hence, anti-angiogenic therapies that target the abnormal vessels and restore the angiogenic-angiostatic balance are candidates for treatment of HHT. Here we review the experimental evidence for dysregulated angiogenesis in HHT, the anti-angiogenic therapeutic strategies used in animal models and some patients with HHT and the potential benefit of the anti-angiogenic treatment for ameliorating this severe, progressive vascular disease. © 2015 Ardelean and Letarte. Source

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