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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; proliferation ; CELL ; PROTEIN ; TUMORS ; DNA ; MECHANISM ; MESSENGER-RNA ; breast cancer ; BREAST-CANCER ; METASTASIS ; TARGETS ; METHYLATION ; TRANSCRIPTIONAL REPRESSOR ; SIGNATURE ; CTCF
    Abstract: Estrogen receptor alpha (ER alpha) upregulation causes abnormal cell proliferation in about two thirds of breast cancers, yet understanding of the underlying mechanisms remains incomplete. Here, we show that high expression of the microRNA miR-375 in ER alpha-positive breast cell lines is a key driver of their proliferation. miR-375 overexpression was caused by loss of epigenetic marks including H3K9me2 and local DNA hypo-methylation, dissociation of the transcriptional repressor CTCF from the miR-375 promoter, and interactions of ER alpha with regulatory regions of miR-375. Inhibiting miR-375 in ER alpha-positive MCF-7 cells resulted in reduced ERa activation and cell proliferation. A combination of expression profiling from tumor samples and miRNA target prediction identified RASD1 as a potential miR-375 target. Mechanistic investigations revealed that miR-375 regulates RASD1 by targeting the 3' untranslated region in RASD1 mRNA. Additionally, we found that RASD1 negatively regulates ER alpha expression. Our findings define a forward feedback pathway in control of ER alpha expression, highlighting new strategies to treat ER alpha-positive invasive breast tumors.
    Type of Publication: Journal article published
    PubMed ID: 20978187
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  • 2
    Abstract: DNA methylation patterns have been recognised as cancer-specific markers with high potential for clinical applications. We aimed at identifying methylation variations that differentiate between breast cancers and other breast tissue entities to establish a signature for diagnosis. Candidate genomic loci were analysed in 117 fresh-frozen breast specimens, which included cancer, benign and normal breast tissues from patients as well as material from healthy individuals. A cancer-specific DNA methylation signature was identified by microarray analysis in a test set of samples (n = 52, p 〈 2.1 x 10(-4)) and its performance was assessed through bisulphite pyrosequencing in an independent validation set (n = 65, p 〈 1.9 x 10(-7)). The signature is associated with SFRP2 and GHSR genes, and exhibited significant hypermethylation in cancers. Normal-appearing breast tissues from cancer patients were also methylated at these loci but to a markedly lower extent. This occurrence of methylated DNA in normal breast tissue of cancer patients is indicative of an epigenetic field defect. Concerning diagnosis, receiver operating characteristic curves and the corresponding area under the curve (AUC) analysis demonstrated a very high sensitivity and specificity of 89.3 and 100 %, respectively, for the GHSR methylation pattern (AUC 〉0.99). To date, this represents the DNA methylation marker of the highest sensitivity and specificity for breast cancer diagnosis. Functionally, ectopic expression of GHSR in a cell line model reduced breast cancer cell invasion without affecting cell viability upon stimulation of cells with ghrelin. Our data suggest a link between epigenetic down-regulation of GHSR and breast cancer cell invasion.
    Type of Publication: Journal article published
    PubMed ID: 22899222
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  • 3
    Publication Date: 2011-09-23
    Description: Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Najmabadi, Hossein -- Hu, Hao -- Garshasbi, Masoud -- Zemojtel, Tomasz -- Abedini, Seyedeh Sedigheh -- Chen, Wei -- Hosseini, Masoumeh -- Behjati, Farkhondeh -- Haas, Stefan -- Jamali, Payman -- Zecha, Agnes -- Mohseni, Marzieh -- Puttmann, Lucia -- Vahid, Leyla Nouri -- Jensen, Corinna -- Moheb, Lia Abbasi -- Bienek, Melanie -- Larti, Farzaneh -- Mueller, Ines -- Weissmann, Robert -- Darvish, Hossein -- Wrogemann, Klaus -- Hadavi, Valeh -- Lipkowitz, Bettina -- Esmaeeli-Nieh, Sahar -- Wieczorek, Dagmar -- Kariminejad, Roxana -- Firouzabadi, Saghar Ghasemi -- Cohen, Monika -- Fattahi, Zohreh -- Rost, Imma -- Mojahedi, Faezeh -- Hertzberg, Christoph -- Dehghan, Atefeh -- Rajab, Anna -- Banavandi, Mohammad Javad Soltani -- Hoffer, Julia -- Falah, Masoumeh -- Musante, Luciana -- Kalscheuer, Vera -- Ullmann, Reinhard -- Kuss, Andreas Walter -- Tzschach, Andreas -- Kahrizi, Kimia -- Ropers, H Hilger -- England -- Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, 19857 Tehran, Iran.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21937992" target="_blank"〉PubMed〈/a〉
    Keywords: Brain/metabolism/physiology ; Cell Cycle ; Cognition Disorders/*genetics ; Consanguinity ; DNA Mutational Analysis ; Exons/genetics ; Gene Regulatory Networks ; Genes, Essential/genetics ; Genes, Recessive/*genetics ; *High-Throughput Nucleotide Sequencing ; Homozygote ; Humans ; Intellectual Disability/*genetics ; Metabolic Networks and Pathways ; Mutation/genetics ; Organ Specificity ; Synapses/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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