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Kristensen V.N.,Institute for Cancer Research
EMBO Molecular Medicine | Year: 2011

Since the luminal B tumours are associated with poor recurrence-free and disease-specific survivals in all adjuvant systemic treatment categories including hormone therapy, the identification of specific signalling pathways driving luminal B biology is paramount to improve treatment. Sircoulomb et al. and Holland et al. have independently identified the ZNF703 gene, located in chromosomal region 8p12, as preferentially amplified in luminal B tumours. © 2011 EMBO Molecular Medicine.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development.RESULTS: We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma.CONCLUSIONS: This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.

Wesche J.,Institute for Cancer Research
Molecular Cancer Research | Year: 2010

The fibroblast growth factor receptors (FGFR) play essential roles both during development and in the adult. Upon ligand binding, FGFRs induce intracellular signaling networks that tightly regulate key biological processes, such as cell proliferation, survival, migration, and differentiation. Deregulation of FGFR signaling can thus alter tissue homeostasis and has been associated with several developmental syndromes as well as with many types of cancer. In human cancer, FGFRs have been found to be deregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. In this review, we will give an overview of the main FGFR alterations described in human cancer to date and discuss their contribution to cancer progression. ©2010 AACR.

Folkerd E.J.,Institute for Cancer Research | Dowsett M.,Breakthrough Breast Cancer Research Center
Journal of Clinical Oncology | Year: 2010

To review the influence of sex hormones on the progression of breast, prostate, gynecologic, and colorectal cancer. The literature was reviewed in an informal manner utilizing the authors' prior knowledge to collate the current evidence for the involvement of sex hormones, particularly estrogens and androgens in the progression of a range of hormonally responsive cancers. In particular, the effect of treatment involving hormone withdrawal treatment was considered strong evidence for involvement. The impact of basal levels of endogenous steroids was considered. Data from clinical trials indicate the efficacy of therapeutic interventions that result in ablation or antagonism of host steroids for a range of cancers. Demonstration of the correlation of the completeness of withdrawal with clinical outcome together with direct evidence of progression from studies looking at the influence of tissue and circulating levels of sex hormones more recently in conjunction with gene expression profiles all provide compelling evidence for the involvement of steroids in the progression of disease. The involvement of steroids in the progression of cancer in hormone-sensitive tissues is well established and an important target for therapy. © 2010 by American Society of Clinical Oncology.

Sioud M.,Institute for Cancer Research
New Biotechnology | Year: 2010

Since its discovery in the late 1990s by Fire and Mello, RNA interference (RNAi) has proven a useful tool for scientists working in the fields of functional genomics, biotechnology, and therapeutic development. However, one of the obstacles of making small interfering RNAs (siRNAs), the main effector of RNAi, a therapeutic agent includes the activation of the immune system, off-target effects, and competition with endogenous microRNAs (miRNAs) for cellular miRNA-processing machinery. Therefore, the translation of RNAi technology into the clinic depends on the development of new strategies to surmount siRNA unwanted effects and identify siRNA sensing receptors as well as to understand the extend of the competition between exogenous and endogenous miRNAs. This minireview summarizes our current knowledge of siRNA sensing by the immune receptors and how to separate siRNA unwanted effects from gene silencing. © 2010 Elsevier B.V. All rights reserved.

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