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Dawson S.-J.,University of Cambridge | Rueda O.M.,University of Cambridge | Aparicio S.,University of British Columbia | Aparicio S.,British Columbia Cancer Research Center | And 2 more authors.
EMBO Journal | Year: 2013

Breast cancer is a group of heterogeneous diseases that show substantial variation in their molecular and clinical characteristics. This heterogeneity poses significant challenges not only in breast cancer management, but also in studying the biology of the disease. Recently, rapid progress has been made in understanding the genomic diversity of breast cancer. These advances led to the characterisation of a new genome-driven integrated classification of breast cancer, which substantially refines the existing classification systems currently used. The novel classification integrates molecular information on the genomic and transcriptomic landscapes of breast cancer to define 10 integrative clusters, each associated with distinct clinical outcomes and providing new insights into the underlying biology and potential molecular drivers. These findings have profound implications both for the individualisation of treatment approaches, bringing us a step closer to the realisation of personalised cancer management in breast cancer, but also provide a new framework for studying the underlying biology of each novel subtype. © 2013 European Molecular Biology Organization.

Olive P.L.,British Columbia Cancer Research Center
Radiotherapy and Oncology | Year: 2011

The application of biological responses of tumours to predict clinical responses to treatment represents a challenging goal with the potential to inform treatment decisions and improve outcome. If tumour cell death is the result of the inability of a cell to repair complex DNA damage, and if γH2AX foci mark sites of unrepaired double-strand breaks, then it may be possible to use residual γH2AX foci to identify treatment-resistant tumour cells early in the course of therapy. This review will highlight some of the evidence that supports the idea that residual γH2AX foci, within certain limitations, may be useful as an early indicator of tumour response to radiotherapy in situ, either alone or in combination with chemotherapy. © 2011 Elsevier Ireland Ltd. All rights reserved.

Evdokimova V.,Institute of Protein Research | Tognon C.E.,British Columbia Cancer Research Center | Sorensen P.H.B.,British Columbia Cancer Research Center | Sorensen P.H.B.,University of British Columbia
Seminars in Cancer Biology | Year: 2012

Translational regulation is increasingly recognized as a critical mediator of gene expression. It endows cells with the ability to decide when a particular protein is expressed, thereby ensuring proper and prompt cellular responses to environmental cues. This ability to reprogram protein synthesis and to permit the translation of the respective regulatory messages is particularly important in complex changing environments, including embryonic development, wound healing and environmental stress. Not surprisingly, mistakes in this process can lead to cancer. This review will focus on the mechanisms of translational control operating in normal and cancer cells. We discuss the possibility that progression of primary epithelial tumors into a motile mesenchymal-like phenotype during the invasive phase of metastasis is driven, in part, by a switch from cap-dependent to cap-independent translation. © 2012 Elsevier Ltd.

Tognon C.E.,British Columbia Cancer Research Center | Sorensen P.H.B.,British Columbia Cancer Research Center
Expert Opinion on Therapeutic Targets | Year: 2012

Introduction: The IGF system controls growth, differentiation, and development at the cellular, organ and organismal levels. IGF1 receptor (IGF1R) signaling is dysregulated in many cancers. Numerous clinical trials are currently assessing therapies that inhibit either growth factor binding or IGF1R itself. Therapeutic benefit, often in the form of stable disease, has been reported for many different cancer types. Areas covered: Canonical IGF signaling and non-canonical pathways involved in carcinogenesis. Three recent insights into IGF1R signaling, namely hybrid receptor formation with insulin receptor (INSR), insulin receptor substrate 1 nuclear translocation, and evidence for IGF1R/INSR as dependence receptors. Different approaches to targeting IGF1R and mechanisms of acquired resistance. Possible mechanisms by which IGF1R signaling supports carcinogenesis and specific examples in different human tumors. Expert opinion: Pre-clinical data justifies IGF1R as a target and early clinical trials have shown modest efficacy in selected tumor types. Future work will focus upon assessing the usefulness or disadvantages of simultaneously targeting the IGF1R and INSR, biomarker development to identify potentially responsive patients, and the use of IGF1R inhibitors in combination therapies or as an adjunct to conventional chemotherapy. © 2012 Informa UK, Ltd.

Ma Q.C.,University of British Columbia | Ma Q.C.,British Columbia Cancer Research Center | Ennis C.A.,British Columbia Cancer Research Center | Aparicio S.,University of British Columbia | Aparicio S.,British Columbia Cancer Research Center
Current Opinion in Genetics and Development | Year: 2012

Recent advances in next generation sequencing have greatly enhanced the scope and speed of genomic cancer research. Apart from merely listing identified mutations from cancer genomes sequencing, this review will summarize some insights specifically focusing on the biology of allele generating cancer driver mutations and clonal patterns during tumor evolution. Studies using massively parallel sequencing of primary tumor samples and cancer cell lines have identified neomorphic alleles and other recurrent mutations in proteins involved in chromatin modification and in the regulation of transcription and translation. Further studies with deep sequencing of matched primary and metastatic tumors have also started to characterize distinct patterns of tumor clonal evolution. The development of single cell sequencing is expected to help further elucidate tumor clonality and aid the translation of these discoveries into diagnostic and therapeutic applications. © 2012 Elsevier Ltd.

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