bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitumoral Activity of 3rd Generation Derivative Lobaplatin in In Vitro Models of Triple-Negative Breast Cancers.
Authors: Honig A. , Martens T. , Häusler S. , Buchholz S. , Rack B. , Wishhusen J. , Dietl J. , Engel J. 
Published: December 2010

Abstract
Introduction:Triple-negative breast cancers are characterized by aggressive growth and early metastasic spread. Some preliminary clinical data have demonstrated good anti-tumor activity of platinum derivatives. 3rd generation compound Lobaplatin* has shown a favorable toxicity profile as compared to Cisplatin. We therefore evaluated this compound in in vitro models of triple negative breast cancers.Study design:Triple-negative humane breast cancer cell lines HCC 1937 and HCC 1806 were treated with increasing concentrations of Lobaplatin and Cisplatin (0,16-10 μm). Cells were incubated for 24, 48 and 72 h with both substances in serum-free and serum-containing medium, in order to evaluate cytotoxic effects in proliferating as well as in metabolically inactive cells. Induction of apoptosis was tested by cleavage of PARP and Caspase 3 as demonstrated by western blot analysis. Subsequently cells were coincubated with Lobaplatin and multi-caspase inhibitor ZVAD-fmk, in order to check if cell death induced by Lobaplatin can be abrogated by inhibition of classical apoptosis. Cytotoxic effects were evaluated by crystal-violet assay. To investigate in which phase of the cell cycle cytotoxicity is most pronounced, cell cycle FACS analysis was performed after treatment with various concentrations of Lobaplatin.Results:Lobaplatin showed a somewhat better anti-tumor activity in both cell lines than Cisplatin. Lobaplatin Induced cleavage of PARP and procaspase 3 indicative for induction of classical apoptosis. However, cytotoxic effects of Lobaplatin were not decreased by multi-caspase inhibitor ZVAD-fmk. Cell-cycle FACS analysis showed, that sub-G0/1 fraction (indicactive for apoptotic/necrotic cells) was increased and G2 fraction was decreased dose-dependently by treatment with Lobaplatin.Conclusion:Lobaplatin showed a good anti-tumor activity in in vitro models of triple negative breast cancers which was at least equal to Cisplatin. Main mechanism of ytotoxicity was programmed cell death, which could not be abrogated by multi-caspase inhibition. Due to the good anti-tumor activity and the favorable toxicity profile, Lobaplatin should be considered for clinical studies in triple negative breast cancers.*Aeterna/Zentaris GmbH, Frankfurt/M
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6115.
MicroRNA Expression Profiling of Inflammatory Breast Cancer.
Authors: Lerebours F. , Clairac G. , Tozlu-Kara S. , Vacher S. , Lidereau R. , Bieche I. 
Published: December 2010

Abstract
Background: IBC (Inflammatory Breast Cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, gene alterations specific to IBC remain to be identified. Emerging data suggest that microRNAs, a small class of non-coding RNAs able to regulate gene expression, are dysregulated in certain types of cancer and may therefore serve as tool for diagnosis and prediction. We aimed to determine a miRNA expression profiling (microRNAome) in IBC.Methods: We measured the miRNA expression levels of 936 miRNAs by using real-time quantitative RT-PCR in a well-defined series of 12 IBCs (stage T4d according to UICC classification), by comparison with 31 non stage-matched non inflammatory breast cancers (stage I to non inflammatory IIIB) and 8 normal breast tissues.Results: 573 microRNAs were retained for analysis (Ct &lt; 32). Among these 573 miRNAs, 31 were significantly up-regulated (p&lt;0,05 and fold-change &gt; 2,5) in IBC compared with both non IBC and normal breast tissues. Five of the 31 up-regulated miRNAs were also significantly up-regulated in non IBC versus normal tissues. Eleven of the 31 up-regulated miRNAs showed fold-changes greater than 4 times between IBC and non IBC: miR-1308, miR-503, miR-1234, miR-1247, miR-612, miR-671, miR-1825, miR-1306, miR-99, miR-7-1, and miR-937.The expression levels of the 31 up-regulated candidate miRNAs are currently being measured using real time QRT-PCR in a new larger independent prospective series of 66 IBC collected in our institution between jul-03 and dec-08. Sixty-six non stage-matched non inflammatory breast tumor tissues are used as controls.Conclusions: This study represents the first analysis of miRNA expression in IBC. It may serve as a basis for functional studies of the role of miRNAs in the etiology of IBC.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6118.
Transcriptional Profile Changes Induced by Rapamycin in Breast Cancer Maintained in Organ Culture.
Authors: Grosso S. , Katayama M. , Roela R. , Nonogaki S. , Soares F. , Brentani M. , Goes J. 
Published: December 2010

Abstract
Background: mTOR (mammalian target of rapamycin) is a serine threonine kinase, member of the AKT/PI3K pathway, which is involved in multiple biologic functions such as transcription, translation, protein degradation and ribosome biogenesis. The activation of this protein results in phosphorilation and activation of S6K1 and 4EBP1. Rapamycin is a potent fungicide, immunossupressive and anti-cancer agent that inhibits the mTOR pathway and is an emerging cancer therapeutic. Objective: The aim of this study was to determine genes regulated by rapamycin in samples of ductal invasive breast cancer to identify novel markers of rapamycin response. Material and Methods: Inhibition of some elements of AKT pathway was assessed by immunohistochemistry in samples of breast carcinoma maintained in organ culture of fresh cut slices that preserves the interaction between epithelium and stroma before and after treatment with rapamycin. Additionally changes of the gene expression profile was analyzed by microarray in these samples subdivided in positive and negative Erb-B2. Results: Immunohistochemistry analysis indicated a significant decrease of 4EBP1 in the samples of tumor treated with rapamycin compared with the control cases. Microarray analysis revealed that few common genes were regulated in both tumor types but rapamycin affected the expression of genes mainly involved in cellular transcription and translation in both groups. To confirm the results obtained through microarray technique, RT-PCR analysis was performed in independent samples and we validated the genes WWOX, EXT1 and GTF2E2 in 60% of our cases. Over expression of the autophagy related beclin 1 indicated a contribution of autophagy to cytotoxicity of rapamycin. Conclusion: The organ culture represents a simple method to determine the effects of rapamycin and using gene profile analysis, novel genes that possible could be used as markers of mTOR inhibition were identified. Supported by FAPESP nº 04/04607-8
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6129.
Molecular Subtype Profile Reveals Therapy Predictive Power.
Authors: de Snoo F. , Krijgsman O. , Roepman P. , Bender R. , Glas A. 
Published: December 2010

Abstract
BackgroundClassification of breast cancers into molecular subtypes may be important for accurate selection of therapy for patients. Here we report the respective chemotherapy responsiveness of the molecular subtypes profile defined Luminal, ERBB2 and Basal type.MethodsAn 80-gene subtype profile was developed based on a series of 200 samples with concordant ER, PR and Her2 receptor IHC and single gene readout status. Previously we reported the excellent validation of the profile classification using 784 samples. Here we report a second in silico validation consisting of 133 samples (Hess et al, JCO, 2006) which tested the profile as a predictor of pathological Complete Response (pCR) in these patients treated with T/FAC neoadjuvant chemotherapy.ResultsIn the 133 publicly available samples the profile classified 62% (82) as Luminal-type, 18% (24) as ERBB2-type and 20% (27) as Basal-type. These results were consistent with percentages found in the training and validation cohorts (n=1079; 295 training and 784 validation samples); 66% (712) Luminal-type, 18% (194) as ERBB2-type and 16% (173) Basal-type. Chemotherapy response was measured by pathological Complete Response (pCR) at the time of surgery In the Luminal-type subgroup 9% (7) of patients showed pCR, in the ERBB2-type subgroup 50% (12) of patients had a pCR and in the Basal-type subgroup 56% (15) of patients had a pCR.ConclusionsThe developed multi-gene profile can classify breast cancer tumors into Luminal-, ERBB2- and Basal-type subgroups. Within the subgroups, a significant difference in chemotherapy response, as measured by pCR, is observed. Implementation of this knowledge may improve the clinical management of breast cancer patients, by enabling the physician to decide who is most likely to benefit from chemotherapy or endocrine therapy prior to surgery.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6131.
Determination of Molecular Profiles of BRCA1 and BRCA2 Breast Cancers.
Authors: Banneau G. , Guedj M. , Schiappa R. , Petel F. , Sevenet N. , De Mascarel I. , Mac Grogan G. , Longy M. , Bonnet F. 
Published: December 2010

Abstract
BackgroundBRCA1 and BRCA2 genes are known to be the target of germline mutations in familial breast cancers, which represent 5% of the total breast cancer population. Mutation screening of these genes is performed in suspected familial breast cancer cases but a causative mutation is found in only 30% of patients. Therefore the development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1 - or BRCA2 - mutated breast cancers.Material and MethodsArray-CGH and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the bases of at least 3 affected first degree relatives or at least 2 affected first degree relatives with breast cancer at an average age of 45 years. Tumoral DNA was co-hybridized with pooled normal blooded DNA from 21 individuals on a 4407 BAC-array (CIT-V8) provided by the CIT program and manufactured by Integragen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Clinical, pathological and genomic data were retrieved through Annotator, the CIT cancer database and the analysis was performed by using the R statistical software along with the CIT R packages.ResultsUsing supervised clustering analyses we identified 2 transcriptomic signatures, one for BRCA1-mutated breast cancers consisting of 600 probes sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined CGH-array signatures, based on a presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers.ConclusionThis study has identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. Moreover, we identified specific genomic rearrangements in these breast cancers which could be screened for in a diagnostic setting using FISH thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6132.
Stage 2 Genome-Wide Association Study of Candidate Low Penetrance Genes Implicated in Breast Cancer Risk.
Authors: Ross G. , Johnson N. , Fletcher O. , Orr N. , Hosking F. , Ashworth A. , dos Silva Santos I. , Lathrop M. , Houlston R. , Peto J. 
Published: December 2010

Abstract
The risk of breast cancer in the first-degree female relatives of breast cancer cases is approximately double the risk in the general population. BRCA1 and BRCA2 account for less than 20% of this excess risk; the majority is probably due to the multiplicative effects of large numbers of low penetrance risk alleles. Genome-wide association studies (GWAS) have successfully identified 13 low-penetrance breast cancer risk alleles (Easton et al 2007, Hunter et al 2007, Stacey et al 2007, Zheng et al 2009, Ahmed et al 2009, Thomas et al 2009) but power calculations suggest that many more are still to be discovered.We have recently conducted a genome wide association study of 1,500 bilateral breast cancer cases, 200 cases with at least two affected first degree relatives and 1,450 controls from the 1958 birth cohort (WTCCC, 2007) using the Illumina HumanHap 370 chip. Based on these data and publicly available data from the Cancer Genetic Markers of Susceptibility (CGEMS) study we have selected 1,200 of the most significant SNPs to genotype in a stage 2 study comprising 5,500 breast cancer cases and 4,500 controls. All 13 of the known loci were replicated in this 2-stage analysis.Additional candidates at novel genomic loci are being genotyped in a replication study of 6,000 cases and 6,000 controls.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6136.
Differential Gene Expression Profiles in Breast Cancer Tumors from Young and Post-Menopausal Patients.
Authors: Moreira-Filho C. , Ramos P. , Ramos P. , Barreta L. , Brentani H. , Corradini B. , Maciel M. , Carraro D. , Achatz M. , Michelli R. , Lyra E. , Grosso S. , Folgueira M. , Katayama M. , Brentani M. 
Published: December 2010

Abstract
Breast cancer in young patients (&lt;35 yrs) has been hypothesized to be more histologically aggressive than those occurring in older cohorts, based mainly in their histopahtological features and worse prognosis. Our current knowledge of the genes involved in such differences is limited. To obtain insight into the molecular processes underlying tumorigenesis in young women we have used 44K cDNA microarrays (Agilent) to compare the gene expression profiles of 30 samples obtained from patients younger than 35 years (median 32,5, range 25-35) and 19 post-menopausal patients (median 66, range 55-88 ), all of them with ductal invasive carcinoma. Both age groups showed similar incidence of ER and PR-positive cases (70 and 60%, respectively). We considered as differentially expressed genes those presenting a p value below 0.01(t test) and fold variation of+/- 2.5.Gene ontology was performed using the GOTree machine tool (GOTM). By such criteria, 121 genes (86% down-regulated) were identified between the two groups here analyzed. In tumors arising in younger women we found an overrepresentation of genes involved with G-protein receptor signaling,cytoskeleton and muscle development, including ankyrin 3,filamin B, gfsarcoglycan and small proline- rich protein, one of the cornified-envelope structural precursor protein. In addition, solely in the younger women set we compared the gene profiles between women with (n =19) or without (n = 10) familial history of breast carcinoma. Using the same criteria, 59 transcripts distinguished the two subsets: GO categories over represented in tumors from patients with familial history included cell-cell adhesion, cytoskeleton organization,cell motility and protein binding related genes. These results indicate that breast cancer tumors arising in young women, besides their uniqueness regarding tumorigenesis, also differ among familial and non-familial cases as revealed by gene expression profiles.Support: FAPESP 04/14029-1
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6138.
Gene Transcripts in the Tumor Suppressor Region of Chromosome 3 (3p21).
Authors: Al Sarakbi W. , Sasi W. , Jiang W. , Roberts T. , Newbold R. , Mokbel K. 
Published: December 2010

Abstract
Background:There is increasing evidence that the short arm of chromosome 3 has a tumour suppressor region that has been associated with permanent growth arrest of tumour cells. We have identified 9 closely related genes in this region (CCDC12, KLH9, KLH18, MYL3, NBEAL2, PTPN23, SCAP, SETD2, and TESSP2) located which could be possible candidates for tumour suppressor genes (TSG).Our objective was to determine, using quantitative PCR, whether the mRNA expression levels of these genes were consistent with a tumour suppressive function in human breast cancer.Methods:A total of 153 samples were analysed. The levels of transcription of all 9 genes were determined using quantitative PCR and normalized against (CK19).Transcript levels within breast cancer specimens were compared with non-cancerous breast tissue and analyzed against conventional pathological parameters and clinical outcome over a 10 year follow-up period.Results:Quantification of CCDC12, KLH9, KLH18, MYL3, NBEAL2, PTPN23, and SCAP mRNA expression after CK19 normalisation showed no statistically significant difference between malignant and normal breast tissue (p=0.23, 0.46, 0.3, 0.141, 0.8, 0.696, and 0.11 respectively). The mRNA expression of TESSP2 was higher in normal samples compared with malignant lesions (347 vs. 35, p=0.0061) but showed no significant associations with clinical outcome.The levels of SETD2 mRNA were significantly lower in malignant samples (406 vs. 17, p=0.0345) and decreased with increasing tumour stage. SETD2 expression levels were significantly lower in samples from patients who developed metastasis, local recurrence, or died from breast cancer when compared to those who were disease free for &gt; 10 years (p=0.041).Conclusion:These findings are consistent with a possible tumour suppressor function of SETD2 in human breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6139.
Genes Regulating the Progression of Human Ductal Carcinoma In Situ to Invasive Breast Cancer.
Authors: Lee S. , Wu Y. , Dao B. , Lim A. , Medina D. , Stewart S. , Allred D. 
Published: December 2010

Abstract
Rationale: The progression of human ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) represents a major potentially life-threatening event. Our understanding of this process is rudimentary. Improved understanding could lead to better ability to predict and new therapeutic strategies to prevent progression, which would be major contributions to health care. Objectives: To identify genes involved in regulating the progression of human DCIS to IBC, and to confirm their involvement utilizing relevant in vitro and in vivo model systems. Methods: Gene expression profiles were evaluated in five complimentary cohorts of human DCIS and IBC (total n=59 in each category) using cDNA microarray technology. Supervised statistical comparisons were used to identify differentially expressed genes in each cohort. The genes were distilled to top priority candidates by the following vetting strategy: (1) expression changed in same direction in 2 or more cohorts; and (2) they possessed known biological functions which might reasonably be involved in regulating tumor invasion; and (3) they had not been studied in the context of breast cancer invasion. Initial studies have focused on candidate invasion-suppressor genes (down-regulated in IBC vs. DCIS). A human DCIS-like cell line (DCIS.COM) was stably transduced with shRNAi against the genes (3-5 hairpins each) and evaluated in vitro and in vivo for changes in invasion-related behaviors vs. controls (growth and migration in 2D and 3D cell cultures, invasion in 3D culture, and a human-in-mouse [HIM} DCIS xenograft model). The latter is a novel method we developed where cells are injected into the nipple duct of intact mammary glands of immune-compromised mice. They initially grow as DCIS which progress to IBC at varying rates depending on the cells. Results: Two novel invasion-suppressor genes (CSTA and FAT1) were identified based on demonstrating significantly increased growth, migration, and invasion in the assays described. In particular, shCSTA (n=22) and shFAT1 (n=22) HIM DCIS xenografts progressed to large IBCs by 10 weeks or less, significantly (P&lt;.0001) greater than observed in controls (n=26) (67%, 64%, vs. 26%, respectively). Conclusions: We have identified two genes (CSTA and FAT1) whose normal functions appear to suppress the progression of human DCIS to IBC. These results could lead to new therapeutic strategies to prevent or suppress progression.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6141.
SRC-1 Promotes Breast Cancer Metastasis by Activating MAPK Pathway.
Authors: Qin L. 
Published: December 2010

Abstract
Background: Steroid receptor coactivator (SRC-1) was defined as a nuclear receptor coactivator. It interacts with nuclear receptor and other transcriptional factors and promotes target genes expression. In breast cancer, SRC-1 expression correlates positively with HER2 expression, disease recurrence and resistance to endocrine therapy. Our previous work demonstrated that knockout of SRC-1 in mice suppressed breast cancer metastasis without affecting primary tumor initiation and growth in the MMTV-PyMT transgenic mice. However, the molecular mechanism responsible for SRC-1 in breast cancer metastasis is still unclear.Material and Methods: To further study the function of SRC-1 in breast cancer metastasis, we generated transgenic mice with overexpression of human SRC-1 in the mouse mammary epithelial cells. The mammary glands of these mice exhibited normal development. After crossing these mice with MMTV-TVA (avian subgroup A receptor gene, TVA) transgenic mice, we obtained MMTV-TVA/MMTV-hSRC-1 (tester) and MMTV-TVA/WT (control) biogenic mice. RCAS (avian leukosis virus) viruses, which contain MMTV-PyMT expression cassette and can bind to TVA, were injected into mammary gland to induce mammary tumor. Tumor initiation, growth and metastasis were carefully examined with these mice. To investigate mechanism, multiple PyMT tumor cell lines were generated form individual primary tumor with or without SRC-1 and cell migration and invasion were compared with those cells and human breast cancer cells.Results and discuss: No difference in tumor initiation and growth was observed in those mice, but metastasis incidence of breast cancer to lung increased significantly in PyMT/TVA/hSRC-1 mice compared with PyMT/TVA/WT control mice. Tumor metastasis in lung also presented higher index in PyMT/TVA/hSRC-1 mice. In vitro study with PyMT/SRC-1 WT and KO cell lines showed SRC-1 deficiency disturbed cells migration and invasion. WT tumor cells adhered faster to extracellular matrix fibronecetin (FN) and presented high levels of phosphorylated forms of FAK, c-Src, Erk, Jnk and activated Rac1. Western blotting and real-time RT-PCR revealed lower integrin alpha5 and Gem, one of GTP binding protein, levels in SRC-1 deficient tumor cells. In human breast cancer MDA-MB-231 cells, SRC-1 knockdown led to decreased cell migration and invasion. Therefore, SRC-1 may regulate integrin expression and MAPK pathway to promote cancer cell migration and metastasis. Our study provides a possibility to inhibit breast cancer metastasis by targeting SRC-1 function.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6150.