EMS1 amplification can occur independently of CCND1 or INT-2 amplification at 11q13 and may identify different phenotypes in primary breast cancer

Hui, Rina; Campbell, Douglas Houghton; Lee, Christine S. L.; McCaul, Kieran; Horsfall, Debbie; Musgrove, Elizabeth A.; Daly, Roger J.; Seshadri, Ram; Sutherland, Robert L.

doi:10.1038/sj.onc.1201311

Cited by 88 publications

(80 citation statements)

References 22 publications

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“…In the poor survival subgroup, we also observed at chromosome 11q13 two areas of gain marked by CCND1, FGF3, and EMS1 genes. Interestingly, all these genes have been associated with different tumors; [16][17][18] in particular, EMS1 amplification and overexpression was related to poor prognosis in breast cancer 19 and disease progression in esophageal squamous cell carcinoma. 20 A DNA gain at chromosome 20q is the most frequent chromosomal aberration described in esophageal adenocarcinoma, being found in up to 60% of cases.…”

Section: Discussionmentioning

confidence: 99%

“…However, when the total number of chromosomal imbalances was correlated to patient survival, a significant association (P ¼ 0.002) between the total number of gains/losses and survival was found. In particular, by dividing the patients according to their median survival time (20 months), we found that the mean number of quantitatively altered genes per tumor was 20.7 (range 6-33) in patients with a survival r20 months (17 patients), compared to 10.1 (range [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] in patients with a survival 420 months (16 patients) ( Table 2). Similarly, stratification of the patients according to the median number of chromosomal imbalances (12 aberrations), showed a good association with survival (P ¼ 0.014).…”

Section: Association Between Copy Number Alterations and Survival In mentioning

confidence: 99%

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DNA copy number alterations correlate with survival of esophageal adenocarcinoma patients

et al. 2009

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Despite recent advances in surgical and multidisciplinary treatment, prognosis for patients with esophageal adenocarcinoma remains poor, and the low prognostic significance of pTNM staging suggests that additional parameters are needed. To identify genomic abnormalities characteristic of esophageal adenocarcinoma, a panel of 33 samples obtained at surgery from previously untreated patients were analyzed by muliplex ligationdependent probe amplification technique. We detected frequent gains of 6p, 8q, 13q, 17q, 20q, and losses of 4q, 5q, 15q, and 18q. When DNA copy number changes were correlated to clinicopathological features of patients no association was found between the number of chromosomal aberrations and gender, age, tumor grade or pTNM staging. However, interestingly, a significant correlation between patient survival and total number of chromosomal aberrations was found when esophageal adenocarcinoma cases were stratified according to the median of survival (20 months) (P ¼ 0.002) or the median of aberrations (12 aberrations) (P ¼ 0.014). Evaluation of the distribution of gains and losses at the level of single chromosomes indicated that gains on chromosomes 5, 6, 8, 11, 20 and losses on chromosomes 1, 3, 5, 11, and 18 were significantly different in the two survival groups. Furthermore, when single gene imbalances were analyzed in further details, we found that besides alterations that involve genes shared by both survival groups, a few genes (KIAA0170, EMS1, ABCC4, F3, and MIF) were altered only in samples from patients with poor survival. Thus, we established a good correlation between the total number of chromosomal alterations and survival, suggesting that the estimation of total imbalances might represent an additional indicator of disease outcome. In addition, the finding of alterations specific for the more aggressive esophageal adenocarcinoma subset might represent promising biomarkers to increase the accuracy of clinical outcome prediction.

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Section: Discussionmentioning

confidence: 99%

Section: Association Between Copy Number Alterations and Survival In mentioning

confidence: 99%

DNA copy number alterations correlate with survival of esophageal adenocarcinoma patients

et al. 2009

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“…Cortactin-Amplification of EMS1 is associated with poor patient prognosis in ER-negative, but not ER-positive, breast cancers (17). In order to identify proteins interacting with the cortactin SH3 region in ER-negative breast cancer cells, we performed affinity chromatography on 35 S-labeled lysates from MDA-MB-231 cells.…”

Section: Identification Of Proteins Binding To the Sh3 Domain Ofmentioning

confidence: 99%

“…The gene encoding cortactin, EMS1, localizes to chromosomal locus 11q13, a region commonly amplified in breast cancers and squamous cell carcinomas of the head and neck (17,18). The functional properties of cortactin suggest a link with tumor invasion and/or metastasis, and this is supported by the observation that overexpression of cortactin increases cell motility and invasion in vitro (5,19) and enhances bone metastasis of MDA-MB-231 breast cancer cells in a nude mouse model (20).…”

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confidence: 99%

A Cortactin-CD2-associated Protein (CD2AP) Complex Provides a Novel Link between Epidermal Growth Factor Receptor Endocytosis and the Actin Cytoskeleton

Lynch

Winata

Lyons

et al. 2003

Journal of Biological Chemistry

208

194

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Growth factor regulation of the cortical actin cytoskeleton is fundamental to a wide variety of cellular processes. The cortical actin-associated protein, cortactin, regulates the formation of dynamic actin networks via the actin-related protein (Arp)2/3 complex and hence is a key mediator of such responses. In order to reveal novel roles for this versatile protein, we used a proteomics-based approach to isolate cortactin-interacting proteins. This identified several proteins, including CD2-associated protein (CD2AP), as targets for the cortactin Src homology 3 domain. Co-immunoprecipitation of CD2AP with cortactin occurred at endogenous expression levels, was transiently induced by epidermal growth factor (EGF) treatment, and required the cortactin Src homology 3 domain. The CD2AP-binding site for cortactin mapped to the second of three proline-rich regions. Because CD2AP is closely related to Cbl-interacting protein of 85 kDa (CIN85), which regulates growth factor receptor down-regulation via complex formation with Cbl and endophilin, we investigated whether the CD2AP-cortactin complex performs a similar function. EGF treatment of cells led to transient association of Cbl and the epidermal growth factor receptor (EGFR) with a constitutive CD2AP-endophilin complex. Cortactin was recruited into this complex with slightly delayed kinetics compared with Cbl and the EGFR. Immunofluorescence analysis revealed that the EGFR, CD2AP, and cortactin co-localized in regions of EGF-induced membrane ruffles. Therefore, by binding both CD2AP and the Arp2/3 complex, cortactin links receptor endocytosis to actin polymerization, which may facilitate the trafficking of internalized growth factor receptors.Subcellular compartmentalization and trafficking of signal transduction complexes and a variety of dynamic cellular responses to extracellular stimuli require regulated interactions between specific components of signaling pathways and the cytoskeleton. These interactions may be direct or mediated by particular adaptor or scaffolding proteins. Among these, cortactin was identified as a v-Src substrate associated with the cortical actin cytoskeleton approximately a decade ago, although insights into its cellular function and the underlying mechanisms have only been obtained recently (1).In line with an adaptor role, cortactin is a multidomain protein, with the individual modules capable of mediating specific protein-protein interactions (1). The N-terminal region mediates binding to the Arp 1 2/3 complex, a highly conserved regulator of the assembly and structure of actin networks (2), and contains a DDW motif characteristic of Arp2/3-interacting proteins such as WASP, Myo3p, and ActA (2, 3). This is followed by six and a half copies of a 37-amino acid repeat, with the fourth repeat necessary for binding to F-actin in vitro (2). Downstream of the repeats is a predicted helical domain and a region rich in serine, threonine, and proline residues. The latter is a target for both tyrosine and serine/threonine phosphorylation (4 -6)....

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“…Clinical studies have demonstrated that elevated cortactin levels correlate with poor prognosis or relapse in patients (Hui et al, 1997;Rodrigo et al, 2000). Cortactin interacts with F-actin, promoting the activation of the Arp2/3 complex to facilitate branching of actively polymerizing actin bundles and the generation of stress fibers (Mullins, 2000;Urono et al, 2001;Weaver et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells

et al. 2006

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Using a validated tetracycline (tet)-regulated MCF7-founder (MCF7F) expression system to modulate expression of CD44 standard form (CD44s), we report the functional importance of CD44s and that of a novel transcriptional target of hyaluronan (HA)/CD44s signaling, EMS1/cortactin, in underpinning breast cancer metastasis. In functional experiments, tet-regulated induction of CD44s potentiated the migration and invasion of MCF7F cells through HA-supplemented Matrigel. EMS1/cortactin was identified by expression profiling as a novel transcriptional target of HA/CD44 signaling, an association validated by quantitative PCR and immunoblotting experiments in a range of breast cancer cell lines. The mechanistic basis underpinning CD44-promoted transcription of EMS1/cortactin was shown to be dependent upon a NFjB mechanism, since pharmacological inhibition of IjKinase-2 or suppression of p65 Rel A expression attenuated CD44-induced increases in cortactin mRNA transcript levels. Overexpression of a c-myc tagged murine cortactin construct in the weakly invasive, CD44-deficient MCF7F and T47D cells potentiated their invasion. Furthermore, the functional importance of cortactin to CD44s-promoted metastasis was demonstrated by selective suppression of cortactin in CD44-expressing MCF7F-B5 and MDA-MB-231 breast cancer cells using RNAi, which was shown to result in attenuated CD44-promoted invasion and CD44-promoted adhesion to bone marrow endothelial cells (BMECs).

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EMS1 amplification can occur independently of CCND1 or INT-2 amplification at 11q13 and may identify different phenotypes in primary breast cancer

Cited by 88 publications

References 22 publications

DNA copy number alterations correlate with survival of esophageal adenocarcinoma patients

DNA copy number alterations correlate with survival of esophageal adenocarcinoma patients

A Cortactin-CD2-associated Protein (CD2AP) Complex Provides a Novel Link between Epidermal Growth Factor Receptor Endocytosis and the Actin Cytoskeleton

Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells

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