Molecular Oncology RSS feed: Current Issue. Molecular Oncology highlights new discoveries, approaches, as well as technical developments, in basic, clinical and discovery-driven translational research. Topics include: • Key biological processes such as cell cycle; DNA repair; apoptosis; invasion and metastasis; angiogenesis and lymphangiogenesis; cell signalling and interactive networks; immune response. • Emerging technologies (genomics, proteomics, functional genomics, metabolomics, tissue arrays, imaging), and model systems. •Biomarkers: diagnosis, prognosis, stratification and efficacy. • Cancer genetics, epigenetics, and genomic instability. • Minimal residual disease, pre-malignant lesions. • Cancer micro-environment. • Molecular pathology. • Tumour immunology. • Translational research. • Cancer therapy (target discovery, drug design, immunotherapy, combination therapies, resistance, and individualised treatment). • Chemotherapy, radiotherapy and surgery. • Clinical pharmacology. • Clinical trials, integration of basic science into cancer clinical trials. • Epidemiology and prevention. • Infrastructures (biobanks, databases, genomic resources). A main feature of the Journal is to provide an international forum for debating cancer issues, and for integrating the input of all the stakeholders. Coverage: Reviews, original articles, technical notes, editorials, news & views (commentary, science policy issues, ethical and legal issues, patient organisations, industry needs and alliances, regulatory issues, news items), letters to the editor, conference announcements, advertisements. Submitting Authors: Manuscripts can be submitted to Molecular Oncology at: http://ees.elsevier.com/molonc/ http://www.moloncol.org/?rss=yesElsevier Inc.en © 2010 Published by Elsevier Inc. All rights reserved. Molecular Oncology1574-789143June 2010 © 2010 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.moloncol.org/article/PIIS1574789110000396/abstract?rss=yesEditorial Board10.1016/S1574-7891(10)00039-6Molecular Oncology 4, 3 (2010)2010-06-01Molecular Oncology2010-06-0143S1574-7891(10)X0003-5iiiihttp://www.moloncol.org/article/PIIS1574789110000293/abstract?rss=yesBreast cancer (BC), like all cancers is considered to be a genetic disease in the sense that both germline and somatic mutations may be the cause of tumour initiation and development. Our molecular understanding of the role of cancer associated genes and gene products has evolved over the past 20 years. Some gene mutations are linked to inherited cancer syndromes, while other genetic alterations have been found to be associated with certain morphological stages. Furthermore, the type and location of mutations in certain genes have been associated with response to therapy and poor disease outcome. Although part of the genetic «makeup» of patients with elevated cancer risk has been identified, as well as part of the genetic «makeup» of primary breast carcinomas, several issues remain unresolved. The questions of which changes are necessary and which are sufficient for the initiation and progression of a primary tumour as well as its response to therapy are mainly unanswered. Since both germline and somatic mutations are involved in tumour initiation, development, and progression, it should in principle be possible to derive a complete catalogue of inherited and acquired mutations to fully understand the functional consequences of these alterations, and to use that information to develop and implement preventative and more effective interventional strategies. The challenge lies in the complexity of the disease as BC is a multifaceted biological system and hence needs to be attacked by means of systems biology approaches. This complexity arises, in part, from the fact that breast tumours are composite organ systems with dynamic genomes shaped by gene aberrations, cellular biological context, characteristics specific to the individual patient, and environmental influences. The biological dynamics of BC, as well as the interaction with host factors and environmental factors need to be understood at a more fundamental level than that of today. In this thematic issue, an overview of our present knowledge of the molecular biology of breast cancer is presented, highlighting some of the most active research areas and discussing the status as well as future perspectives of the research on this complex disease.On the molecular biology of breast cancerAnne-Lise Børresen-Dale, Therese Sørlie, Vessela N. Kristensen10.1016/j.molonc.2010.04.007Molecular Oncology 4, 3 (2010)2010-05-03Molecular Oncology2010-05-0343S1574-7891(10)X0003-5Preface171173http://www.moloncol.org/article/PIIS1574789110000335/abstract?rss=yesAbstract: Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high penetrance mutations, as well as moderate and low-penetrance genetic variants implicated in breast cancer aetiology. We summarize recent discoveries from large collaborative efforts to combine data from candidate gene studies, and to conduct genome-wide association studies (GWAS), primarily in breast cancers in the general population. These findings are compared with results from collaborative efforts aiming to identify genetic modifiers in BRCA1 and BRCA2 carriers. Breast cancer is a heterogeneous disease, and tumours from BRCA1 and BRCA2 carriers display distinct pathological characteristics when compared with tumours unselected for family history. The relationship between genetic variants and pathological subtypes of breast cancer, and the implication of discoveries of novel genetic variants to risk prediction in BRCA1/2 mutation carriers and in populations unselected for mutation carrier status, are discussed.Genetic susceptibility to breast cancerNasim Mavaddat, Antonis C. Antoniou, Douglas F. Easton, Montserrat Garcia-Closas10.1016/j.molonc.2010.04.011Molecular Oncology 4, 3 (2010)2010-05-31Molecular Oncology2010-05-3143S1574-7891(10)X0003-5Reviews174191http://www.moloncol.org/article/PIIS1574789110000268/abstract?rss=yesAbstract: Breast cancer is a heterogeneous disease, comprising multiple entities associated with distinctive histological and biological features, clinical presentations and behaviours and responses to therapy. Microarray-based technologies have unravelled the molecular underpinning of several characteristics of breast cancer, including metastatic propensity and histological grade, and have led to the identification of prognostic and predictive gene expression signatures. Furthermore, a molecular taxonomy of breast cancer based on transcriptomic analysis has been proposed. However, microarray studies have primarily focused on invasive ductal carcinomas of no special type. Owing to the relative rarity of special types of breast cancer, information about the biology and clinical behaviour of breast cancers conveyed by histological type has not been taken into account. Histological special types of breast cancer account for up to 25% of all invasive breast cancers. Recent studies have provided direct evidence of the existence of genotypic–phenotypic correlations. For instance, secretory carcinomas of the breast consistently harbour the t(12;15) translocation that leads to the formation of the ETV6–NTRK3 fusion gene, adenoid cystic carcinomas consistently display the t(6;9) MYB–NFIB translocation and lobular carcinomas consistently show inactivation of the CDH1 gene through multiple molecular mechanisms. Furthermore, histopathological and molecular analysis of tumours from conditional mouse models has provided direct evidence for the causative role of specific genes in the genesis of specific histological special types of breast cancer. Here we review the associations between the molecular taxonomy of breast cancer and histological special types, discuss the possible origins of the heterogeneity of breast cancer and propose an approach for the identification of novel therapeutic targets based on the study of histological special types of breast cancer.Histological types of breast cancer: How special are they?Britta Weigelt, Felipe C. Geyer, Jorge S. Reis-Filho10.1016/j.molonc.2010.04.004Molecular Oncology 4, 3 (2010)2010-04-26Molecular Oncology2010-04-2643S1574-7891(10)X0003-5Reviews192208http://www.moloncol.org/article/PIIS1574789110000281/abstract?rss=yesAbstract: Triple-negative breast cancers (TNBC), characterized by absence of estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of human epidermal growth factor receptor 2 (HER2), are typically associated with poor prognosis, due to aggressive tumor phenotype(s), only partial response to chemotherapy and present lack of clinically established targeted therapies. Advances in the design of individualized strategies for treatment of TNBC patients require further elucidation, by combined ‘omics’ approaches, of the molecular mechanisms underlying TNBC phenotypic heterogeneity, and the still poorly understood association of TNBC with BRCA1 mutations. An overview is here presented on TNBC profiling in terms of expression signatures, within the functional genomic breast tumor classification, and ongoing efforts toward identification of new therapy targets and bioimaging markers. Due to the complexity of aberrant molecular patterns involved in expression, pathological progression and biological/clinical heterogeneity, the search for novel TNBC biomarkers and therapy targets requires collection of multi-dimensional data sets, use of robust multivariate data analysis techniques and development of innovative systems biology approaches.Triple-negative breast cancer: Present challenges and new perspectivesFranca Podo, Lutgarde M.C. Buydens, Hadassa Degani, Riet Hilhorst, Edda Klipp, Ingrid S. Gribbestad, Sabine Van Huffel, Hanneke W.M. van Laarhoven, Jan Luts, Daniel Monleon, Geert J. Postma, Nicole Schneiderhan-Marra, Filippo Santoro, Hans Wouters, Hege G. Russnes, Therese Sørlie, Elda Tagliabue, Anne-Lise Børresen-Dale, for the FEMME Consortium10.1016/j.molonc.2010.04.006Molecular Oncology 4, 3 (2010)2010-05-03Molecular Oncology2010-05-0343S1574-7891(10)X0003-5Reviews209229http://www.moloncol.org/article/PIIS1574789110000311/abstract?rss=yesAbstract: Micro-RNAs (miRs) are a recently described class of genes, encoding small non-coding RNA molecules, which primarily act by down-regulating the translation of target mRNAs. miRs are involved in a range of normal physiological processes, notably differentiation and cell type determination. It has become apparent that they are also key factors in cancer, playing both oncogenic and tumour-suppressing roles. We discuss here what is known of miR biology in the normal breast, and of their emerging roles in breast cancer.Micro-RNAs and breast cancerJohn Le Quesne, Carlos Caldas10.1016/j.molonc.2010.04.009Molecular Oncology 4, 3 (2010)2010-05-10Molecular Oncology2010-05-1043S1574-7891(10)X0003-5Reviews230241http://www.moloncol.org/article/PIIS1574789110000244/abstract?rss=yesAbstract: Epigenetic changes can be defined as stable molecular alterations of a cellular phenotype such as the gene expression profile of a cell that are heritable during somatic cell divisions (and sometimes germ line transmissions) but do not involve changes of the DNA sequence itself. Epigenetic phenomena are mediated by several molecular mechanisms comprising histone modifications, polycomb/trithorax protein complexes, small non-coding or antisense RNAs and DNA methylation. These different modifications are closely interconnected. Epigenetic regulation is critical in normal growth and development and closely conditions the transcriptional potential of genes. Epigenetic mechanisms convey genomic adaption to an environment thereby ultimately contributing towards given phenotype. In this review we will describe the various aspects of epigenetics and in particular DNA methylation in breast carcinogenesis and their potential application for diagnosis, prognosis and treatment decision.The epigenetics of breast cancerJovana Jovanovic, Jo Anders Rønneberg, Jörg Tost, Vessela Kristensen10.1016/j.molonc.2010.04.002Molecular Oncology 4, 3 (2010)2010-05-10Molecular Oncology2010-05-1043S1574-7891(10)X0003-5Reviews242254http://www.moloncol.org/article/PIIS1574789110000232/abstract?rss=yesAbstract: Breast cancer is a heterogeneous disease, appreciable by molecular markers, gene-expression profiles, and most recently, patterns of genomic alteration. In particular, genomic profiling has revealed three distinct patterns of DNA copy-number alteration: a “simple” type with few gains or losses of whole chromosome arms, an “amplifier” type with focal high-level DNA amplifications, and a “complex” type marked by numerous low-amplitude changes and copy-number transitions. The three patterns are associated with distinct gene-expression subtypes, and preferentially target different loci in the genome (implicating distinct cancer genes). Moreover, the different patterns of alteration imply distinct underlying mechanisms of genomic instability. The amplifier pattern may arise from transient telomere dysfunction, although new data suggest ongoing “amplifier” instability. The complex pattern shows similarity to breast cancers with germline BRCA1 mutation, which also exhibit “basal-like” expression profiles and complex-pattern genomes, implicating a possible defect in BRCA1-associated repair of DNA double-strand breaks. As such, targeting presumptive DNA repair defects represents a promising area of clinical investigation. Future studies should clarify the pathogenesis of breast cancers with amplifier and complex-pattern genomes, and will likely identify new therapeutic opportunities.Genomic instability in breast cancer: Pathogenesis and clinical implicationsKevin A. Kwei, Yvonne Kung, Keyan Salari, Ilona N. Holcomb, Jonathan R. Pollack10.1016/j.molonc.2010.04.001Molecular Oncology 4, 3 (2010)2010-04-20Molecular Oncology2010-04-2043S1574-7891(10)X0003-5Reviews255266http://www.moloncol.org/article/PIIS1574789110000323/abstract?rss=yesAbstract: Defining the pathways through which tumors progress is critical to our understanding and treatment of cancer. We do not routinely sample patients at multiple time points during the progression of their disease, and thus our research is limited to inferring progression a posteriori from the examination of a single tumor sample. Despite this limitation, inferring progression is possible because the tumor genome contains a natural history of the mutations that occur during the formation of the tumor mass. There are two approaches to reconstructing a lineage of progression: (1) inter-tumor comparisons, and (2) intra-tumor comparisons. The inter-tumor approach consists of taking single samples from large collections of tumors and comparing the complexity of the genomes to identify early and late mutations. The intra-tumor approach involves taking multiple samples from individual heterogeneous tumors to compare divergent clones and reconstruct a phylogenetic lineage. Here we discuss how these approaches can be used to interpret the current models for tumor progression. We also compare data from primary and metastatic copy number profiles to shed light on the final steps of breast cancer progression. Finally, we discuss how recent technical advances in single cell genomics will herald a new era in understanding the fundamental basis of tumor heterogeneity and progression.Tracing the tumor lineageNicholas E. Navin, James Hicks10.1016/j.molonc.2010.04.010Molecular Oncology 4, 3 (2010)2010-05-13Molecular Oncology2010-05-1343S1574-7891(10)X0003-5Reviews267283http://www.moloncol.org/article/PIIS157478911000027X/abstract?rss=yesAbstract: Chemoresistance remains the main reason for therapeutic failure in breast cancer as well as most other solid tumours. While gene expression profiles related to prognosis have been developed, so far use of such signatures as well as single markers has been of limited value predicting drug resistance. Novel technologies, in particular with regard to high through-put sequencing holds great promises for future identification of the key “driver” mechanisms guiding chemosensitivity versus resistance in breast cancer as well as other malignant conditions.Molecular basis for therapy resistancePer E. Lønning10.1016/j.molonc.2010.04.005Molecular Oncology 4, 3 (2010)2010-05-03Molecular Oncology2010-05-0343S1574-7891(10)X0003-5Reviews284300http://www.moloncol.org/article/PIIS1574789110000220/abstract?rss=yesAs much training as a physician has in the complexities and nuances of a disease like cancer, nothing can prepare them for the labyrinthine rules and twisted economics that occur at the hazy crossroads where pharmaceutical manufacturers and insurance companies meet. Nowhere is this more true than in America, which is the world's most important single market for drugs, as well as it's most expensive.The cost of hope: Doctors weigh the benefits of new drugs against sky-high costsSamuel Loewenberg10.1016/j.molonc.2010.03.003Molecular Oncology 4, 3 (2010)2010-03-24Molecular Oncology2010-03-2443S1574-7891(10)X0003-5News & Views301303