Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures

INTRODUCTION: Breast cancer subtyping and prognosis have been studied extensively by gene expression profiling, resulting in disparate signatures with little overlap in their constituent genes. Although a previous study demonstrated a prognostic concordance among gene expression signatures, it was limited to only one dataset and did not fully elucidate how the different genes were related to one another nor did it examine the contribution of well-known biological processes of breast cancer tumorigenesis to their prognostic performance. METHOD: To address the above issues and to further validate these initial findings, we performed the largest meta-analysis of publicly available breast cancer gene expression and clinical data, which are comprised of 2,833 breast tumors. Gene coexpression modules of three key biological processes in breast cancer (namely, proliferation, estrogen receptor [ER], and HER2 signaling) were used to dissect the role of constituent genes of nine prognostic signatures. RESULTS: Using a meta-analytical approach, we consolidated the signatures associated with ER signaling, ERBB2 amplification, and proliferation. Previously published expression-based nomenclature of breast cancer 'intrinsic' subtypes can be mapped to the three modules, namely, the ER-/HER2- (basal-like), the HER2+ (HER2-like), and the low- and high-proliferation ER+/HER2- subtypes (luminal A and B). We showed that all nine prognostic signatures exhibited a similar prognostic performance in the entire dataset. Their prognostic abilities are due mostly to the detection of proliferation activity. Although ER- status (basal-like) and ERBB2+ expression status correspond to bad outcome, they seem to act through elevated expression of proliferation genes and thus contain only indirect information about prognosis. Clinical variables measuring the extent of tumor progression, such as tumor size and nodal status, still add independent prognostic information to proliferation genes. CONCLUSION: This meta-analysis unifies various results of previous gene expression studies in breast cancer. It reveals connections between traditional prognostic factors, expression-based subtyping, and prognostic signatures, highlighting the important role of proliferation in breast cancer prognosis.Journal ArticleMeta-AnalysisResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Meta-analysis of gene-expression profiles in breast cancer: towards a unified understanding of breast cancer sub-typing and prognosis signatures

San Antonio Breast Cancer Conference - SABCS - December 2007 - San Antonio, Tx USAabstract 1047info:eu-repo/semantics/publishe

Nucleolar Integrity Is Required for the Maintenance of Long-Term Synaptic Plasticity

<div><p>Long-term memory (LTM) formation requires new protein synthesis and new gene expression. Based on our work in <i>Aplysia</i>, we hypothesized that the rRNA genes, stimulation-dependent targets of the enzyme Poly(ADP-ribose) polymerase-1 (PARP-1), are primary effectors of the activity-dependent changes in synaptic function that maintain synaptic plasticity and memory. Using electrophysiology, immunohistochemistry, pharmacology and molecular biology techniques, we show here, for the first time, that the maintenance of forskolin-induced late-phase long-term potentiation (L-LTP) in mouse hippocampal slices requires nucleolar integrity and the expression of new rRNAs. The activity-dependent upregulation of rRNA, as well as L-LTP expression, are poly(ADP-ribosyl)ation (PAR) dependent and accompanied by an increase in nuclear PARP-1 and Poly(ADP) ribose molecules (pADPr) after forskolin stimulation. The upregulation of PARP-1 and pADPr is regulated by Protein kinase A (PKA) and extracellular signal-regulated kinase (ERK)—two kinases strongly associated with long-term plasticity and learning and memory. Selective inhibition of RNA Polymerase I (Pol I), responsible for the synthesis of precursor rRNA, results in the segmentation of nucleoli, the exclusion of PARP-1 from functional nucleolar compartments and disrupted L-LTP maintenance. Taken as a whole, these results suggest that new rRNAs (28S, 18S, and 5.8S ribosomal components)—hence, new ribosomes and nucleoli integrity—are required for the maintenance of long-term synaptic plasticity. This provides a mechanistic link between stimulation-dependent gene expression and the new protein synthesis known to be required for memory consolidation.</p></div

Forskolin-induced increase of PARP-1 and pADPr requires the ERK pathway.

<p>Left column (A, C, E): Representative Western blots used for quantification shown in right column (B, D, F). Phosphorylation of the ERK pathway substrate S6K was used as a stimulation-dependent positive control quantified as the ratio of p-S6K to total S6K (A, B). Histone 2B was used as a loading control (C, E). Fsk treatment (black bar) produced an increase of p-S6K, PARP-1, and pADPr (B, D, and F, respectively). The Fsk induced increase was prevented by the ERK inhibitor U0126 (grey bar; B, D, F). The inhibitor alone had no effect on PARP-1 or pADPr levels (striped bar; D, F respectively) compared with basal controls (white bar; D, F). Student's t-test (B,D,F); * = p<0.05; ** = p<0.01; NS = not significant.</p

PAR inhibitor 3-AB produces changes in nucleolar fibrillarin intensity in cultured hippocampal neurons.

<p>DAPI staining (blue; A, B, G and H) shows the area of nuclei. Nomarski images (grey; E and F) show the area of the nuclei and nucleoli (arrowheads). (I) 3-AB treatment (100 µM, 3h) has no effect on the average area of the nucleolar marker fibrillarin (green). (J) In contrast, there was an increase in the average intensity of fibrillarin that was ∼1.6 fold stronger than control; compare arrowheads A,C,G to B, D,H. Bar = 10 µm (A–F) and 2 µm (G, H). Student's t-test ** = p<0.01; NS = not significant.</p

PAR is required for Fsk-induced synthesis of new rRNAs.

<p>(A) Fsk treatment upregulates unedited precursor rRNA (ht rRNA) (black bar) 1.8 fold in hippocampal slices compared with untreated controls (white bar). This increase is prevented when PAR is blocked by 3-AB (grey bar). (B) The PARP-1 dependent immediate-early gene <i>c-jun</i>, was used as a positive control. Student's t-test; * = p<0.05; ** = p<0.01.</p

Forskolin-induced PARP-1 and pADPr increase requires PKA activity.

<p>Left column (A, C, E): Representative Western blots used for quantification shown in right column (B, D, F). Phosphorylation of the PKA pathway substrate S6K was used as a stimulation-dependent positive control quantified as the ratio of p-S6K to total S6K (A, B). Histone 2B was used as a loading control (C, E). Fsk treatment (black bar) produced an increase of p-S6K, PARP-1, and pADPr (B, D, and F, respectively). The Fsk induced upregulation of both PARP-1 and pADPr was prevented by the PKA inhibitor KT5720 (grey bar; B, D, F). The inhibitor alone had no effect on PARP-1 or pADPr levels (striped bar; D, F respectively) compared with basal controls (white bar; D, F). Student's t-test (B,D,F); * = p<0.05; ** = p<0.01; NS = not significant.</p

Low-dose Act-D treatment blocks LTP maintenance.

<p>(A) The maintenance of LTP is blocked by low-dose (45 min, 100 nM) Act-D treatment. (B) Quantification of the change in LTP amplitude 1 and 2 h after initiating Fsk treatment. Representative fEPSP traces for times a, b, and c (from A) appear above bars. Student-Newman-Keuls test ** = p<0.01.</p