Identification of brain- and bone-specific breast cancer metastasis genes

Klein, Andreas; Olendrowitz, Christian; Schmutzler, Rita; Hampl, Juergen A.; Schlag, Peter M.; Maass, Nicolaì; Arnold, Norbert; Wessel, Ralf; Ramser, Juliane; Meindl, Alfons; Scherneck, Siegfried; Seitz, Susanne

doi:10.1016/j.canlet.2008.11.017

Cited by 104 publications

(86 citation statements)

References 34 publications

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“…These niches form as a result of factors secreted by tumor and stroma cells, and can either be newly induced or be adaptations of pre-existing physiological niches, such as stem cell niches of hematopoietic organs [1,5]. Thus, the gene signature associated with poor prognosis facilitates the emergence of metastatic cells in the primary tumor, but the specific set of genes associated with bone metastasis seems responsible for the cellular activities necessary for metastatisation [6][7][8]. For completeness, the metastatic capacity might be considered as a late, acquired event in tumorigenesis and during secondary growth, through epigenetic control of transcription [9,10].…”

Section: Introductionmentioning

confidence: 99%

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Maroni

Matteucci²,

Luzzati³

et al. 2010

Breast Cancer Res Treat

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The aim of the present paper was to identify nuclear co-localization of COX-2 and HIF-1α in human-bone metastasis of breast cancer, index of transcriptionally-activated cells and functional for gene expression. In particular, we verified whether hypoxia exerted a direct role on metastasis-gene expression or through COX-2 signaling, due to the relevance for clinical implications to individuate molecular targets for diagnosis and therapy. The experiments were performed in vitro with two autoregulatory loops triggered a specific array of transcription factors responsible for COX-2 transactivation. The novelty was that HGF and TGF-β1 biological signals were produced by hypoxic metastatic cells and, therefore, the microenvironment seemed to be modified by metastaticcell engraftment in the bone. In agreement, HIF-1α expression in bone-marrow supportive cells occurred in metastasis-bearing animals. Altogether, the data supported the pre-metastatic-niche theory. Our observations might be useful to design therapies against bone metastasis, by affecting the phenotype changes of metastatic cells occurring at the secondary growth site through COX-2-HIF-1 interaction.Keywords bone microenvironment · bone metastasis · breast cancer · COX-2 · HIF-1 3

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Section: Introductionmentioning

confidence: 99%

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Maroni

Matteucci²,

Luzzati³

et al. 2010

Breast Cancer Res Treat

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“…One possibility for this failure could be that the studies were designed to measure outcomes of generalized metastases. Given recent evidence that a large number of MMPs are up-regulated in bone metastases (Kang et al 2003;Nabha et al 2008;Klein et al 2009), primary outcome of bone metastases measurements may have been a more appropriate endpoint to demonstrate clinically significant differences with MMP inhibitors. …”

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confidence: 99%

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Guise

2009

Genes Dev.

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Bone metastases are the most common skeletal complication of malignancy. Tumor cells disrupt normal bone remodeling to promote bone destruction and its associated morbidity. In the August 15, 2009, issue of Genes & Development, Lu and colleagues (pp. 1882-1894) propose a novel molecular mechanism by which tumor-produced metalloproteinases release epidermal growth factor (EGF) ligands to activate the central osteoclastogenic pathway receptor activator of NF-kB ligand (RANKL) to promote breast cancer osteolysis. This work has important therapeutic applications that may quickly translate to more effective treatment for bone metastases.Bone metastases are common in breast, prostate, and lung cancer, and are associated with significant morbidity. Unique aspects of the bone microenvironment-such as mineralized bone matrix, which houses immobilized growth factors, bone-destroying osteoclasts, and boneforming osteoblasts-make it a fertile soil for these cancers to grow. Significant insight into the molecular mechanisms responsible for the proclivity of tumors to metastasize and grow in bone has been gleaned in recent years from mouse models and clinical studies. Bone destruction mediated by solid tumor metastases to bone, particularly in breast cancer, is driven by tumor stimulation of osteoclastic bone resorption. Collective evidence supports the notion that effective therapy for bone metastases should target both the tumor and the bone microenvironment. Indeed, bisphosphonate therapy to block osteoclastic bone resorption, used in conjunction with standard anti-cancer treatments, reduces bone pain, pathologic fracture, and hypercalcemia associated with bone metastases from all tumor types. However, regression and cure of bone metastases have yet to be achieved with the current therapeutic armamentarium. Thus, a better understanding of the molecular mechanisms responsible for this devastating skeletal complication of malignancy is required to develop more effective therapy, with the eventual goal of curing and preventing bone metastases. In the August 15, 2009, issue of Genes & Development, Lu et al. (2009) bring the field closer to this goal. They describe an autocrine/paracrine signaling cascade triggered by metalloproteinases-matrix metalloproteinase-1 (MMP-1) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)-and cleavage of epidermal growth factor (EGF) ligands to reduce the ratio of osteoblast-produced receptor activator of NF-kB ligand (RANKL) to osteoprotegerin (OPG) to favor osteoclastogenesis and promote breast cancer osteolysis. These studies, described herein, have important implications for new applications of standard cancer therapy that could result in more effective treatment for bone metastases. Bone metastases: clinical features and current therapyCertain solid tumors-such as breast, prostate, and lung cancer-have a propensity to metastasize to bone to cause bone pain, fracture, hypercalcemia, and paralysis. This morbidity is great: Up to 75% of advanced breast and prostate c...

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“…For the generation of Figure 2, CorrXpression Software was used [28][29]. Only the 121 top-ranked transcripts were used for the correspondence plot.…”

Section: Methodsmentioning

confidence: 99%

Gene Expression Profiling of Pancreatic Cancer Reveals a Significant Deregulation of the TGF-β Pathway and the Discovery of Genes for Prognosis

Klein¹,

Pospisil²

2014

Global J. Hum. Genet. Gene Ther.

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Abstract:We have re-analyzed previously published gene expression data from ninety-four pancreatic ductal adenocarcinomas (PDAC) samples. We determined the gene expression profile of genes differentially expressed in PDAC compared to non-malignant pancreatic tissue. Using the 100 top-ranked genes, we were able to discriminate between PDAC and non-malignant pancreatic tissue. A hierarchical cluster analysis revealed only a 6 % false discovery rate. The prognostic strength of these discriminative genes was underscored by a SVM classification and 3-fold cross validation with an 89 % correct class assignment. The annotation of the 100 top-ranked genes revealed that most of the genes were involved in the processes of signal transduction, cell adhesion, extracellular matrix organization and cell migration. The most greatly affected signal cascade was the transforming growth factor receptor signaling pathway, which was significantly enriched in the top-ranked genes. Furthermore, we identified eleven genes that were associated with good prognosis.

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Identification of brain- and bone-specific breast cancer metastasis genes

Cited by 104 publications

References 34 publications

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Gene Expression Profiling of Pancreatic Cancer Reveals a Significant Deregulation of the TGF-β Pathway and the Discovery of Genes for Prognosis

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