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  • American Association for Cancer Research (AACR)  (11)
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  • 1
    Online Resource
    Online Resource
    Abstract P4-09-01: Poly (ADP-ribose) Polymerase-1 mRNA Expression in Human Breast Cancer: Correlations with Subtypes and Prognostic Impact
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 24_Supplement ( 2010-12-15), p. P4-09-01-P4-09-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 24_Supplement ( 2010-12-15), p. P4-09-01-P4-09-01
    Abstract: Introduction: Although poly(ADP-ribose) polymerase-1 (PARP1) inhibition is a recent promising therapy in breast cancer, PARP1 expression in this disease is not known. Methods. Using DNA microarray and array-based comparative genomic hybridization (arrayCGH), we examined PARP1 mRNA expression and copy number alterations in 326 invasive breast cancer samples and normal breast samples. A meta-analysis was performed on a large public retrospective gene expression dataset (n= 2,485) to analyze correlation between PARP1 mRNA expression and molecular subtypes and clinico-pathological parameters. Results. PARP1 was overexpressed in 58% of cancers, and its expression was heterogeneous between tumors. ArrayCGH data revealed an association between mRNA overexpression and gain/amplification at the PARP1 locus (p & lt;1.0E-8). Meta-analysis showed that PARP1 expression was higher in basal breast cancers (p & lt;1.0E-72), but overexpression was also found in other subtypes. PARP1 expression correlated with high grade, medullary histological type, tumor size and worse metastasis-free survival (HR=1.12 [1.04-1.22]; p=0.004). In multivariate analysis, PARP1 expression had an in dependent prognostic value, which was restricted to patients untreated with any adjuvant chemotherapy. Univariate and multivariate analyses in MFS in patients untreated with systemic adjuvant chemotherapy Conclusion. These data demonstrate overexpression of PARP1 in a large number of breast cancers and its association with reduced metastasis-free survival. These results further support the development of PARP inhibitors in basal subtype but also potentially in other breast cancer subtypes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS10-P4-09-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 2
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    Abstract P4-04-04: The mutational profile of inflammatory breast cancer reveals a higher mutational burden leading to MAPK activation and chromatin remodeling
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P4-04-04-P4-04-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P4-04-04-P4-04-04
    Abstract: Introduction. Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer with increased metastatic potential. In the past, we have identified a gene expression profile that characterizes IBC, suggesting that a specific molecular biology underpins this devastating disease. Here, we explore the hypothesis that the molecular portrait of IBC is a reflection of underlying genomic alterations. Materials and Methods. Mutation and copy number variation (CNV) profiles for 663 genes were assembled from 2.352 publicly available primary tumor samples (subtype distribution: 1.520 HR+, 355 HER2+, 414 TNBC and 190 unassigned) including 127 profiles from patients with IBC. Gene-wise differences in the frequency of genomic aberrations between patients with and without IBC, stratified per subtype, were investigated using Chi-square testing with adjustment for multiple comparisons. Genomic perturbation differences of pathways and processes, represented by KEGG or Gene Ontology gene sets, were evaluated by collapsing mutation and CNV profiles across all genes associated with the respective gene sets. Finally, mutational signature (MS) profiles were calculated and compared between patients with and without IBC. Results. Seventy-six genes showed evidence of more extensive genomic alterations in samples from patients with IBC as compared to those without IBC (i.e. false discovery rate & lt; 10%), whereas only 3 genes reveal the opposite pattern. Genes mutated in more than 15% (range 16.2% - 63,5%) of the IBC samples include: AXIN1, ERBB2, ERBB3, CBL, CTNNB1, CYP2D6, FGFR1, INSR, KIT, KMT2A, LRP1B, MYC, PBRM1, SACS, SMAD4, TP53 and ZNF217. Analysis of MS profiles revealed differences for signature 1 (i.e. age-related deamination of 5-methylcytosine), 2 (i.e. APOBEC3 activity), 3 (i.e. defective homologuous recombination), 11 (i.e. alkylating agents), 20 (i.e. DNA mismatch repair) and 24 (i.e. aflatoxin), of which MS 11 and 24 are more active in IBC. When evaluating the same panel of genes in TNBC only, 28 genes were retained, suggesting data are confounded by the subtype distribution. Pathway analysis revealed genomic perturbation of MAPK signaling and chromatin organizational processes in respectively 55% and 74% of TN IBCs. Discussion. These data suggest that IBC is characterized by an extensive mutational burden that results, amongst others in the activation of MAPK signaling as well as chromatin remodeling. The analysis of MS profiles does not provide a clear biological explanation for the increased frequency of genomic alterations in IBC, with APOBEC3 activity, defective homologous recombination, defective DNA mismatch repair and age-related deamination of 5-methylcytosinie all being more prominent in nIBC samples. Notably, the lower frequency of age-related C & gt;T transitions is in line with younger age at diagnosis typical for patients with IBC. Citation Format: Van Laere S, Finetti P, Rypens C, Billet C, Birnbaum D, Vermeulen P, Viens P, Dirix L, Bertucci F. The mutational profile of inflammatory breast cancer reveals a higher mutational burden leading to MAPK activation and chromatin remodeling [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-04-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P4-04-04
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
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    PD03-01: An Integrated Analysis of Three Distinct IBC/nIBC Affymetrix Gene Expression Data Sets Further Unveils the Molecular Biology of IBC.
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 24_Supplement ( 2011-12-15), p. PD03-01-PD03-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. PD03-01-PD03-01
    Abstract: Introduction. Several studies have applied gene expression profiling to inflammatory breast cancer (IBC). Most of these studies were underpowered. Here, we present an integrated analysis of 3 distinct gene expression data sets of IBC and non-IBC (nIBC) samples to further uncover the IBC-specific molecular biology with enhanced statistical power. Materials & Methods. Three Affymetrix gene expression data sets were combined, resulting in a series of 137 IBC and 252 nIBC samples. IBC was diagnosed clinically. Each sample was classified according to several published gene signatures. Transcriptional heterogeneity was investigated using hierarchical clustering, coupled with silhouette score analysis. IBC-specific, molecular subtype-independent differences in gene expression were identified using linear regression modeling. Differentially expressed genes were translated into pathways using Ingenuity Pathway Analysis. Cox regression analysis was used to identify variables influencing distant metastasis-free survival (DMFS) in IBC. Finally, we focussed on the molecular aspects of pathological response to neodjuvant chemotherapy in patients with IBC. Results. In our series of IBC samples, 4 robust sample clusters were identified. These sample clusters were mainly associated with the different molecular subtypes (P & lt;0.0001), all of which were identified in IBC with a similar prevalence in nIBC, except for the Luminal A subtype (9% vs. 40%; P & lt;0.0001) and the ErbB2+ subtype (23% vs. 8%; P=0.0002). A total of 632 genes were differentially expressed. Analysis of this gene list identified an IBC-repressed network centered on TGFβ. Activated TGFβ-profiles and SMAD-profiles in the nIBC samples corroborated these findings. Consistent with published poor prognosis signatures, current survival analysis indicated that the molecular subtypes are significantly associated with prognosis in IBC. Surprisingly, in IBC, the Luminal A samples exhibited the shortest DMFS-interval (HR=4.02; P & lt;0.05). Comparison of responders and non-responders to neoadjuvant chemotherapy suggests a prominent role for inflammation/immunity-related processes in determining the efficacy of neoadjuvant chemotherapy in IBC. Conclusions. IBC, like nIBC, is transcriptionally heterogeneous as exemplified by the identification of 4 robust sample clusters in the present series. This observation is further corroborated by the identification of all known molecular subtypes in IBC, albeit with a different distribution pattern characterized by a low frequency of Luminal A samples. Nevertheless, this phenotype is clinically relevant, as demonstrated by the poor prognosis profile. Our observations can be explained by the IBC-specific repression of TGFβ, which is a key molecule of epithelial-to-mesenchymal transition and is also known to prevent ER-expressing cells from proliferating. Finally, as in nIBC, inflammation- and immunity-related processes are important aspects of response to neoadjuvant chemotherapy in IBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD03-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS11-PD03-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Abstract P5-03-01: Cancer stem cells predict engraftment and poor prognosis of primary breast tumors
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 24_Supplement ( 2012-12-15), p. P5-03-01-P5-03-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 24_Supplement ( 2012-12-15), p. P5-03-01-P5-03-01
    Abstract: Breast cancer is a major health problem and heterogeneity of the disease has been considered as a strong limitation to find the best therapies to cure cancer, overcome recurrences and metastases. The establishment of models that reflect tumor biology and metastatic progression is critical to develop successful new therapeutic strategies. In the breast, orthotopic xenografts currently appear as the best models to study tumor growth, metastasis and develop tools for prognosis prediction. Furthermore, mouse transplant assays have been used to assess cancer stem cell (CSC) activity and demonstrate that leukemia and many solid tumors are organized along a hierarchical model. Despite the promise of the CSC model sustained by mouse transplantation assays, the clinical relevance of xenografts studies to identify determinants of stemness able to influence clinical outcome remains challenging. In breast cancer, transcriptional programs from functionally validated CSC populations remain to be deciphered. Here, we report the establishment of a bank of primary breast tumor-derived xenografts (xenobank). We showed that the xenografts retain the main features of primary tumors, that engraftment is correlated with the presence of CSC in tumors, and that engraftment in the mouse is able to predict prognosis in patients. This suggests that CSCs may govern breast cancer prognosis. We established the gene expression profiles of functionally validated ALDEFLUOR-positive CSC populations (breast CSC-GES) and demonstrated their clinical relevance. Among 2609 patients with breast cancers, we validated that he expression of the breast CSC-GES is correlated with poor outcome and metastasis in uni-and multivariate analysis (5-year MFS was 70% CI95 [67–74] in the breast CSC-positive class and 80% (CI95 [77–83] ) in the breast CSC-negative class (p = 5.5E−04 with log-rank test). Furthermore, we identified a core of 19 genes commonly expressed in breast CSC, murine embryonic, neural and hematopoietic stem cells programs and demonstrated for each gene its ability to modulate breast CSC population, being implicated in self-renewing or differentiation programs. We found that the core of genes in common between four stem cell gene expression studies (CE-BCSC-3SC) displayed an adverse prognostic impact for patients with breast cancer. The core contained genes implicated in oxidative phosphorylation, detoxification, lipid metabolism, and genomic stability, and these shared determinants of stemness influenced clinical outcome. Thus, we show ed that CSCs from orthotopically engrafted primary breast tumors have clinical and biological relevance. This functionally validated CSC population is highly correlated with survival and express genes governing main stem cell functions, substantiating a major prediction of the CSC model and opening further promises for new CSC therapies using valid preclinical models. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS12-P5-03-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 5
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    P5-01-01: Identification, Validation and Assessment of Transcriptional Relevance of a PDGFR-Activation Signature in (Inflammatory) Breast Cancer.
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 24_Supplement ( 2011-12-15), p. P5-01-01-P5-01-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. P5-01-01-P5-01-01
    Abstract: Introduction. Breast cancer can be divided into several subgroups characterized by unique patterns of pathway activation. Platelet-derived growth factor receptor (PDGFR) signalling has not yet been included in this classification scheme, although it has been reported to be a potential target for therapy. In this study, we have constructed a PDGFR-activation signature and investigated its relevance in breast cancer. Materials and Methods. Sixteen PDGFR-modulated genes were identified by intersecting two published PDGFR-modulated gene lists. The resulting gene signature was applied onto a publicly available gene expression data set of GIST (GSE17743) using principle component analysis. The segregation of PDGFR- and KIT-mutated GIST samples was investigated using permutation analysis and classification sensitivity and specificity were assessed. Using the regression coefficients from the first principal component, a PDGFR-activation score was constructed and applied onto a second data set in order to validate the score (GSE1923). Finally, the score was applied onto a gene expression data set of 389 breast cancer ***samples, including 137 samples from patients with IBC. Results. Sixteen PDGFR-modulated genes (NR4A1, EGR3, JUNB, IER3, TIEG, JUN, BCL3, MYC, NR4A3, PLAU, MCL1, DUSP1, DUSP5, DUSP6, SGK, GADD45A) were able to discriminate PDGFR-mutated GIST samples from KIT-mutated GIST samples with a sensitivity of 75% and a specificity of 85%. Application of the PDGFR-activation score onto a data set of control and PDGF-treated glioblastoma cells showed a significant increase in the PDGFR-activation score in the treated condition (P=0.0302). Application of the PDGFR-signature onto our series of IBC and nIBC samples demonstrated a significant and molecular subtype-independent increase in PDGFR-activation in IBC (P=0.0015; FDR=3%). In addition, in our series of nIBC samples only, PDGFR-activation was associated with decreased DMFS and RFS (P=0.0038 and P=0.0137 respectively). In fact, PDGFR-activation was an independent prognosticator in a multivariate model incorporating the molecular subtypes. Discussion. We identified a gene signature composed of 16 genes able to predict PDGFR-activation in tissue samples by gene expression analysis. PDGFR-activation is significantly increased in samples from patients with IBC, an aggressive form of locally advanced breast cancer. In addition, in nIBC, PDGFR-activation is associated with DMFS and RFS, independently of the molecular subtypes suggesting that PDGFR-activation might add another level of clinically relevant heterogeneity in breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS11-P5-01-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 6
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    Abstract P4-13-23: Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH) and patient-derived tumor xenograft (PDX) for precision medicine in advanced breast cancer: A single-center prospective study
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 4_Supplement ( 2016-02-15), p. P4-13-23-P4-13-23
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. P4-13-23-P4-13-23
    Abstract: Background Genomic-based approaches in advanced breast cancer (ABC) were recently demonstrated as feasible in the clinical practice, but only a limited number of patients were actually treated with targeted therapies matching genomic alterations, with low antitumor activity. We conducted a pilot study to evaluate whether precision medicine using NGS and aCGH could be implemented prospectively at a single center in ABC patients. In addition, we examined whether PDX could be derived from ABC and thus could help inform therapeutic decision. Methods ABC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study (ClinicalTrials.gov, NCT01521676). Tumor tissue from locally recurrent or metastatic disease was immediately frozen after dedicated biopsy. Genomic profiling included high-resolution 4x180K aCGH (Agilent Technologies, Massy, France) and DNA sequencing, using a library of 365 cancer candidate genes (HaloPlex target enrichment kit, Agilent technologies, Santa Clara, CA, USA) and MiSeq analyzer (Illumina, San Diego, CA, USA) with 2x150-bp, paired-end at about 300x coverage. In a subset of patients, fresh tumor was implanted orthotopically in humanized cleared fat pads of NSG mice for establishing xenotransplants. Results A total of 34 ABC patients were included, with the following characteristics: median age 54 years (35-77); molecular subtypes: 11 triple-negative (32%), 12 luminal non-HER2 (35%), 4 luminal HER2 (12%), 3 HER2 non-luminal (9%), and 4 unknown (12%); 33 with previous chemotherapy (97%); 22 with previous endocrine treatment (35%); 7 with previous anti-HER2 (21%). Tumor biopsies were obtained from liver (15), skin (6), peritoneum (4), breast (3), node (3), lung (1), pleura (1), and ascitis (1), with a median tumor cellularity of 70% (range 10-90%). aCGH and NGS were available from 34 and 33 patients, respectively. An actionable target was found in 28 patients (82%), corresponding to 66 targets, including 37 mutations (8 in PIK3CA, 7 TP53, 4 ESR1, 2 AKT1, 2 BRCA2, 2 HER2), 22 amplifications (7 for CCND1, 2 CCNE1, 2 FGFR1, 2 IGF1R) and 7 homozygous deletions (3 for PTEN, 2 CDKN2A/B,1 BRCA2, 1 STK11). A targeted therapeutic proposal was possible, either in a clinical trial (N=18, 52%) or using already registered drugs (N=17, 50%). Ten patients actually received a targeted treatment, 1 of them experienced objective response and 1 showed stable disease for more than 6 months. Of 26 patients subjected to mouse implantation, 10 had successful xenografting (6 triple-negative, 2 HER2, 1 luminal non-HER2, 1 subtype non-attributed), with a median time to reach 10 mm of 148 days. These PDX will be used as models to understand the patient's therapeutic response. Conclusion Precision medicine using high-throughput DNA sequencing and aCGH can be implemented at a single center in the context of clinical practice and may allow direct therapeutic proposal in 1/3 of patients, but antitumor activity was minimal. PDX may be obtained in a significant fraction of patients, especially in triple-negative and HER2 subtypes, and could phenotypically complement genomic data. Citation Format: Gonçalves A, Bertucci F, Chaffanet M, Guille A, Garnier S, Adelaide J, Carbuccia N, Brunelle S, Piana G, Cabaud O, Thomassin-Piana J, Paciencia-Gros M, Chereau-Ewald E, Lambaudie E, Sabatier R, Tarpin C, Provansal M, Jalaguier-Coudray A, Extra J-M, Sarran A, Pakradouni J, Viens P, Lopez M, Ginestier C, Charafe-Jauffret E, Birnbaum D. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH) and patient-derived tumor xenograft (PDX) for precision medicine in advanced breast cancer: A single-center prospective study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-23.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS15-P4-13-23
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    Comprehensive Profiling of 8p11-12 Amplification in Breast Cancer
    American Association for Cancer Research (AACR) ; 2005
    In:  Molecular Cancer Research Vol. 3, No. 12 ( 2005-12-01), p. 655-667
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 3, No. 12 ( 2005-12-01), p. 655-667
    Abstract: In human carcinomas, especially breast cancer, chromosome arm 8p is frequently involved in complex chromosomal rearrangements that combine amplification at 8p11-12, break in the 8p12-21 region, and loss of 8p21-ter. Several studies have identified putative oncogenes in the 8p11-12 amplicon. However, discrepancies and the lack of knowledge on the structure of this amplification lead us to think that the actual identity of the oncogenes is not definitively established. We present here a comprehensive study combining genomic, expression, and chromosome break analyses of the 8p11-12 region in breast cell lines and primary breast tumors. We show the existence of four amplicons at 8p11-12 using array comparative genomic hybridization. Gene expression analysis of 123 samples using DNA microarrays identified 14 genes significantly overexpressed in relation to amplification. Using fluorescence in situ hybridization analysis on tissue microarrays, we show the existence of a cluster of breakpoints spanning a region just telomeric to and associated with the amplification. Finally, we show that 8p11-12 amplification has a pejorative effect on survival in breast cancer. (Mol Cancer Res 2005;3(12):655–67)
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-05-0128
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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  • 8
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    P1-04-07: Poly (ADP-Ribose) Polymerase-1 (PARP-1) Is Overexpressed in Human Breast Cancer Stem Cells: Results from a Proteomic-Based Approach.
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 24_Supplement ( 2011-12-15), p. P1-04-07-P1-04-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. P1-04-07-P1-04-07
    Abstract: Introduction: Cancer stem cells (CSC) have been increasingly recognized as playing a major role in various fields of breast tumor biology including carcinogeneis, metastasis and resistance to cytotoxic drugs and radiotherapy. Identification of protein biomarkers associated with breast CSC may help understanding CSC biology as well as identifying novel diagnostics and specific therapeutic targets. 2-D Fluorescence Difference Gel Electrophoresis (2-D DIGE) is a method that labels protein samples with fluorescent dyes before 2-D electrophoresis, enabling accurate analysis of differences in protein abundance between samples. Methods: Using flow cytometry-based ALDEFLUOR assay (ALD), we isolated CSC-enriched (ALD-positive) and non CSC-enriched (ALD-negative) cell populations of MDA-MB-453, a human breast cancer cell line. Total proteins were extracted from both fractions using urea-based buffer and subjected to 2D-DIGE. Differentially expressed spots were excised, proteins were gel-extracted, digested and identified using MALDI-TOF MS (Ultraflex, Brucker Daltonics, Billerica, USA) Results: 2D-DIGE revealed differential expression of various protein spots between ALD-positive and ALD-negative MDA-MB-453 cells. MALDI-TOF MS analysis allowed identification of 11 differentially expressed proteins, among which 7 were down-regulated and 4 were up-regulated in ALD-positive MDA-MB-453 cells, including Poly (ADP-ribose) polymerase-1 (PARP-1). Overexpression of PARP-1 in MDA-MB-453 cells was further confirmed by western blot using specific monoclonal antibody and such an observation was extended to 4 additional human breast cancer cell lines including HCC1937, MDA-MB-436, SUM149 and SUM159. These 5 human breast cancer cells were found to display a limited short-term sensitivity (within the micromolar range) to olaparib, a specific PARP-1 inhibitor. However, a negative correlation was found between the level of overexpression and the ability of olaparib to inhibit the growth of ALD-positive cells. Conclusion: A proteomic-based approach revealed that PARP-1 was up-regulated in ALD-positive, CSC-enriched from various human breast cancer cell lines. Such an overexpression may contribute to clinical resistance to PARP-inhibitors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS11-P1-04-07
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 9
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    Reproductive and Hormonal Risk Factors for Antinuclear Antibodies (ANA) in a Representative Sample of U.S. Women
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 23, No. 11 ( 2014-11-01), p. 2492-2502
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 11 ( 2014-11-01), p. 2492-2502
    Abstract: Background: Autoantibodies are of growing interest in cancer research as potential biomarkers; yet, the determinants of autoimmunity are not well understood. Antinuclear antibodies (ANA) are common in the general population and are more prevalent in women and older adults. Here, we examined the relationship of ANA with reproductive and hormonal factors in a representative sample of U.S. women. Methods: We analyzed data on reproductive history and exogenous hormone use in relation to serum ANA in 2,037 females ages 12 years and older from the National Health and Nutrition Examination Survey (NHANES; 1999–2004). Estimated ANA prevalences were adjusted for sampling weights. Prevalence ORs (POR) and 95% confidence intervals (CI) were adjusted for age, race, and poverty–income ratio, and models were stratified by menopause status. Results: In premenopausal women ages 20 years and older, ANA prevalence was associated with parity (P & lt; 0.001; parous vs. nulliparous POR = 2.0; 95% CI, 1.2–3.4), but in parous women, ANA did not vary by number of births, age at first birth, years since last birth, or breastfeeding. In postmenopausal women, ANA prevalence was associated with an older age at menarche (P = 0.019; age 16–20 vs. 10–12 years POR = 3.0; 95% CI, 1.6–5.9), but not with parity. Oral contraceptives and estrogen therapy were not associated with a higher ANA prevalence. Conclusions: Childbearing (having had one or more births) may explain age-associated elevations in ANA prevalence seen in premenopausal women. Impact: These findings highlight the importance of considering reproductive history in studies of autoimmunity and cancer in women. Cancer Epidemiol Biomarkers Prev; 23(11); 2492–502. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-14-0429
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    Immunohistochemistry-based marker profile accurately predicts risk in operable, hormone receptor-positive patients.
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 2_Supplement ( 2009-01-15), p. 1062-
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 2_Supplement ( 2009-01-15), p. 1062-
    Abstract: Abstract #1062 Background: The performance of current prognostic breast cancer tests is limited, because they only address simple additive molecular risks, and the results are often difficult to interpret in the context of overlapping clinicopathologic risks. Gene expression-based tests can be further confounded by contamination with non-tumor cells. Our goal was to develop a protein-based profile that addresses these limitations. Methods: ER, PR, Her2, EGFR, BCL2, p27/Kip1, and p53 (IHC) and MYC (FISH) were scored in tumor cells of FFPE tissue from patients with operable, pN0-2, hormone receptor-positive breast cancer at two clinical sites. A consensus prognostic model was trained using robust cross-validation in 290 hormone therapy (HT)-treated patients using statistical pattern recognition methods to account for complex marker interactions. Tumor grade, pT, and pN were directly incorporated into the model to the extent they were not replaced by the molecular markers. Continuous risk scores ranging from 0 to 10+ were generated for the 290 HT-treated patients, 90 untreated patients, and 119 patients treated with chemotherapy and HT. Results: A predetermined threshold of 3.8 separated HT-treated patients into high and low risk groups with hazard ratios of 8.8 (p & lt;1E-4) for metastasis and 13.0 (p & lt;1E-4) for disease-specific survival (DSS) without the need for an equivocal intermediate risk group. NPV/PPV were 96%/35% for metastasis at 10 yr and 97%/27% for DSS at 8 yr. In multivariate analyses, the profile was independent and fully replaced the significance of all individual prognostic factors and clinical treatment guideline combinations. Within treatment guideline elevated risk groups (Adjuvant! relapse risk & gt;15%, NPI & gt;3.4, and St. Gallen intermediate/high), the profile reclassified as low risk 84%, 81%, and 85% of pN0 patients, and 43%, 43%, and 32% of pN1 patients, respectively. The reclassified patients had & lt;10% 10-yr metastasis and & lt;5% 8-yr DSS event rates. In HT-treated patients with profile risk scores & gt;7.0, addition of chemotherapy produced a & gt;20% DSS benefit at 8 years (p=0.04). Conclusion: This 8-marker profile with super-additive algorithm achieved significantly higher classification accuracy than treatment guidelines and could aid selection of the most appropriate level of adjuvant therapy in patients with operable breast cancer. & #x2028; & #x2028; Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1062.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS-1062
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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    detail.hit.zdb_id: 410466-3
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