Person: Birkbak, N
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Birkbak
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Birkbak, N
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Publication STAT3 Induction of miR-146b Forms a Feedback Loop to Inhibit the NF- B to IL-6 Signaling Axis and STAT3-Driven Cancer Phenotypes(American Association for the Advancement of Science (AAAS), 2014) Xiang, Michael; Birkbak, N; Vafaizadeh, V.; Walker, Sarah; Yeh, Jennifer; Liu, Suhu; Kroll, Yasmin; Boldin, M.; Taganov, K.; Groner, B.; Richardson, Andrea; Frank, DavidInterleukin-6 (IL-6)–mediated activation of signal transducer and activator of transcription 3 (STAT3) is a mechanism by which chronic inflammation can contribute to cancer and is a common oncogenic event. We discovered a pathway, the loss of which is associated with persistent STAT3 activation in human cancer. We found that the gene encoding the tumor suppressor microRNA miR-146b is a direct STAT3 target gene, and its expression was increased in normal breast epithelial cells but decreased in tumor cells. Methylation of the miR-146b promoter, which inhibited STAT3-mediated induction of expression, was increased in primary breast cancers. Moreover, we found that miR-146b inhibited nuclear factor κB (NF-κB)–dependent production of IL-6, subsequent STAT3 activation, and IL-6/STAT3–driven migration and invasion in breast cancer cells, thereby establishing a negative feedback loop. In addition, higher expression of miR-146b was positively correlated with patient survival in breast cancer subtypes with increased IL6 expression and STAT3 phosphorylation. Our results identify an epigenetic mechanism of crosstalk between STAT3 and NF-κB relevant to constitutive STAT3 activation in malignancy and the role of inflammation in oncogenesis.Publication Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome(American Association for Cancer Research (AACR), 2012) Wang, Z. C.; Birkbak, N; Culhane, Aedin; Drapkin, Ronny; Fatima, Aquila; Tian, R; Schwede, M.; Alsop, K.; Daniels, K. E.; Piao, H.; Liu, Joy; Etemadmoghadam, D.; Miron, A; Salvesen, H. B.; Mitchell, G.; DeFazio, A.; Quackenbush, John; Berkowitz, Ross; Iglehart, James; Bowtell, D. D. L.; Matulonis, UrsulaPurpose—High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. Experimental Design—We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). Results—LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. Conclusions—Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors.Publication MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy(American Association for Cancer Research (AACR), 2015) Neupane, Manish; Clark, Allison; Landini, S.; Birkbak, N; Eklund, A. C.; Lim, E.; Culhane, Aedin; Barry, William T.; Schumacher, Sandra; Beroukhim, Rameen; Szallasi, Zoltan; Vidal, Marc; Hill, David; Silver, Daniel P.An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified MECP2 as a novel oncogene. MECP2 resides in a region of the Xchromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRASG12Caddicted cell line after KRAS down-regulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.Publication A Breast Cancer Meta-Analysis of Two Expression Measures of Chromosomal Instability Reveals a Relationship with Younger Age at Diagnosis and High Risk Histopathological Variables(Impact Journals LLC, 2011) Endesfelder, David; McGranahan, Nicholas; Birkbak, N; Szallasi, Zoltan; Kschischo, Maik; Graham, Trevor A.; Swanton, CharlesBreast cancer in younger patients often presents with adverse histopathological features, including increased frequency of estrogen receptor negative and lymph node positive disease status. Chromosomal instability (CIN) is increasingly recognised as an important prognostic variable in solid tumours. In a breast cancer meta-analysis of 2423 patients we examine the relationship between clinicopathological parameters and two distinct chromosomal instability gene expression signatures in order to address whether younger age at diagnosis is associated with increased tumour genome instability. We find that CIN, assessed by the two independently derived CIN expression signatures, is significantly associated with increased tumour size, ER negative or HER2 positive disease, higher tumour grade and younger age at diagnosis in ER negative breast cancer. These data support the hypothesis that chromosomal instability may be a defining feature of breast cancer biology and clinical outcome.Publication Jetset: Selecting the Optimal Microarray Probe Set to Represent a Gene(BioMed Central, 2011) Li, Qiyuan; Birkbak, N; Gyorffy, Balazs; Szallasi, Zoltan; Eklund, Aron CBackground: Interpretation of gene expression microarrays requires a mapping from probe set to gene. On many Affymetrix gene expression microarrays, a given gene may be detected by multiple probe sets, which may deliver inconsistent or even contradictory measurements. Therefore, obtaining an unambiguous expression estimate of a pre-specified gene can be a nontrivial but essential task. Results: We developed scoring methods to assess each probe set for specificity, splice isoform coverage, and robustness against transcript degradation. We used these scores to select a single representative probe set for each gene, thus creating a simple one-to-one mapping between gene and probe set. To test this method, we evaluated concordance between protein measurements and gene expression values, and between sets of genes whose expression is known to be correlated. For both test cases, we identified genes that were nominally detected by multiple probe sets, and we found that the probe set chosen by our method showed stronger concordance. Conclusions: This method provides a simple, unambiguous mapping to allow assessment of the expression levels of specific genes of interest.