bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational inference of gene expression signatures differentiating between breast cancers responsive or resistant to letrozole.
Authors: Georgieva A , Evans DB , Miller J , Sing T , Dixon J , Miller WR 
Published: December 2010

Abstract
Abstract #3024
Introduction:Genes which have been shown either to be differentially expressed or differentially changed between responders and non-responders to the neoadjuvant treatment with the aromatase inhibitor letrozole have been described. However, their network structure and interconnectivity have not been formally analysed.Bayesian network (BN) inference algorithms have demonstrated promise in the analysis of genomics data to recover fragments of biological pathways due to their ability to capture many types of relationships between variables and to handle noisy data.An inference score (4), normalized to be between -1 and 1, is a measure of the strength of the interaction (either positive or negative) between different nodes in the recovered network.&#x2028; Materials and methods:This computational study uses BN methodology to elucidate any possible network structure and refine a gene expression signature distinguishing responders from non-responders groups to letrozole treatment. It has been applied to 205 covariables (69 baseline expression, 45 day 14 expression and 91 changes in expression with treatment), identified via Random Forests as being differentially expressed between 37 tumours responding to neoadjuvant letrozole and 15 non-responders. The number of false positive relationships was limited by considering 4 different sub-sets of the original data 1) all 205 variables, but allowing for limited connectivity between them; 2) only the baseline variables 3) only the change variables with treatment and 4) only day 14 post-treatment variables. It was conjectured that the variables linking significantly to response status would appear in the overlap between lists 1) and 2), lists 1) and 3) and lists 1) and 4).&#x2028; Results:The analysis of the overall dataset highlighted the importance and the interconnectivity of ribosomal proteins. More specifically, the BN algorithm found two connected networks of 20 genes each with 13 and 14 ribosomal proteins and an average inference score of 0.65. In addition, BN links patient type (responder vs. non-responder) directly to genes that have been implicated in the natural history of breast cancer such as BCL-2 and KIAA0101 with inference scores of 0.4 and 0.45, respectively. The inferred network also contained a link with inference score of 0.4 between patient type and phosphatidylinositol glycan, whose oncogenic role has been suggested by others. The preliminary network analysis of the baseline covariables did not yield any meaningful pattern that differentiates the two patient types, except for the involvement of the cyclin E2 pathway with a “composite” inference score of 0.33.&#x2028; Conclusions: With initial encouraging results, further refinement of the BN analysis, as well as enrichment of the data should facilitate the discovery of a predictive baseline gene expression pattern.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3024.
Prognostic relevance of circulating tumor cells (CTCs) in peripheral blood of breast cancer patients before and after adjuvant chemotherapy – translational research program of the German SUCCESS-trial.
Authors: Schindlbeck C , Rack B , Jueckstock J , Schneeweiss A , Thurner-Herrmanns E , Schneider A , Rezai M , Beckmann M , Pantel K , Lichtenegger W , Sommer H , Friese K , Janni W , Chatsiproios D 
Published: December 2010

Abstract
Abstract #303
Background:&#x2028; The detection of Disseminated Tumor Cells in the Bone Marrow (BM) of Breast Cancer patients has shown prognostic significance in all stages of the disease. An alternative towards BM examination could be the analysis of peripheral blood for Circulating Tumor Cells (CTCs), which has demonstrated prognostic significance in metastatic disease. We analyzed peripheral blood samples from pts. Before and after adjuvant taxane-based chemotherapy as part of the translational research program of the German SUCCESS-trial.&#x2028; Methods: Peripheral blood samples (23 ml each) from 1500 N+ and high risk N- breast cancer pts were analyzed for the presence of CTCs with the CellSearchSystem (Veridex, USA) before and after adjuvant chemotherapy. After automated immunomagnetic enrichment with an anti-Epcam-antibody, cells are labelled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies to distinguish between epithelial cells and leukocytes. Samples are screened automatedly and positive events are visualised on a screen for re-evaluation.&#x2028; Results: In143 pts (10 %) more than 1 CTC was detected before the start of systemic treatment (mean 14, range 2-827). 2 CTCs were found in 4 % of pts, 3 % had 3-5 CTCs and 1 % 6-10 and &gt;10 CTCs, resp. The presence of CTCs did not correlate with tumor size (p=.32), grading (p=.36), hormonal status (p=.28) or Her2 status of the primary tumor (p=.82), but with the presence of lymph node metastases (p=.003). As negative control, three of 74 healthy individuals showed more than 1 CTC.&#x2028; After completion of chemotherapy, 9 % of pts (n=130) presented with &gt;1 CTC (mean 6, range 2-124). Of those initially CTC positive, 10% remained positive (n=15), whereas of those initially CTC negative, 8 % turned positive after chemotherapy (n=115, p=.42).&#x2028; 21 recurrences have been reported during a median follow-up time of 12 months, and 7 pts have died of their disease. While detection of CTCs before systemic treatment did not show prognostic relevance for DFS (p=.89) and OAS (p=.71), presence of CTCs after chemotherapy was a significant predictor for both reduced DFS (p=.04) and OAS (p=.03).&#x2028; Conclusions:&#x2028; Our preliminary results demonstrate prognostic relevance of the presence of CTCs after adjuvant chemotherapy for the first time. Even in the adjuvant setting as well as during follow up, the examination of CTCs could be a valuable tool for monitoring the disease and the effectiveness of therapies. Longer follow-up of the SUCCESS-trial will have to be awaited to confirm these findings.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 303.
Comparative effect of tibolone and its metabolites on sulfatase activity in normal and cancerous breast tissues.
Authors: Pasqualini JR , Chetrite GS , Cortes-Prieto J 
Published: December 2010

Abstract
Abstract #3035
Background: Tibolone (Org OD-14, active substance of Livial®) is a synthetic steroid with a 19-nor-testosterone derivative structure. This compound has weak estrogenic, progestagenic, and androgenic properties and is used to prevent climacteric symptoms and postmenopausal bone loss. Tibolone is extensively metabolized in 3a- and 3ß-hydroxy-derivatives and their 4-en isomer. Previous studies in this laboratory demonstrated that tibolone and its metabolites are anti-sulfatase agents in the hormone-dependent breast cancer cells: MCF-7 and T-47D, while the present study explores their effect on estrone-sulfatase activity in normal and cancerous breast tissues.&#x2028; Materials and Methods: : Two regions of the mammary tissue from each post-menopausal patient with breast cancer (n=8) were selected : the tumoral tissue and a distant zone which was considered as normal. Slices of tumoral or normal breast tissues (25-95 mg) were incubated in buffer (20 mM Tris-HCl, pH 7.2) with physiological concentrations of [3H]-estrone sulfate (E1S) (5x10-9M) alone or in the presence of tibolone or its metabolites (5x10-5 or 5x10-7M) during 14h at 37°C. E1S, estrone and estradiol were characterized by thin layer chromatography and quantified using the corresponding standard.&#x2028; Results: In breast cancer tissues the sulfatase activity was twice as high as in normal breast tissue. At concentrations of 5x10-7 and 5x10-5M tibolone inhibits sulfatase activity in breast cancer tissue by 25 and 33% respectively. Using the same concentrations for the 3a-hydroxy these were 32 and 57%, for the 3ß-hydroxy 22 and 32%, and for 4-en derivatives 0 and 48% respectively. In the normal tissues the values were: for tibolone, 3 and 20%, for the 3a-hydroxy, 16 and 29 %, for the 3ß-hydroxy, 13 and 25%, and for the 4-en derivative 0 and 22% respectively. In these experiments, it was observed that estrone does not convert to estradiol.&#x2028; Conclusion: The present data indicates that the estrone sulfatase activity is higher in breast cancer tissue and that the inhibitory effects of tibolone and its metabolites are significantly higher in this tissue than in the normal breast. It is suggested that the present results can open new possibilities in the knowledge of the mechanism of action of tibolone and its metabolites in normal and cancerous breast.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3035.
MicroRNA-206 expression is down-regulated in estrogen receptor a-positive human breast cancer.
Authors: Kondo N , Toyama T , Sugiura H , Fujii Y , Yamashita H 
Published: December 2010

Abstract
Abstract #3042
There are large-scale molecular differences between estrogen receptor (ER)-positive and ER-negative breast cancers. ERa is essential for estrogen-dependent growth, and its level of expression is a crucial determinant of response to endocrine therapy and prognosis in ER-positive breast cancer. Multiple mechanisms involved in altering ERa gene expression in breast cancer have been identified, including ERa gene amplification as well as transcriptional silencing by DNA methylation of CpG islands within the ERa promoter and mutations within the open reading frame of ERa. However, expression levels of ERa in breast cancer tissues differ widely among patients, and frequently change during disease progression and in response to systemic therapies. Recent evidence has shown that microRNA (miRNA) mutations or mis-expression correlate with various human cancers, and miR-206 is reported to decrease endogenous ERa mRNA and protein levels in human MCF-7 breast cancer cells via two specific target sites within the 3'-untranslated region of the human ERa transcript. In this study, we show that miR-206 expression is markedly decreased in ERa-positive breast cancer tissues assayed by quantitative RT-PCR analysis. We observe that miR-206 expression is inversely correlated with ERa but not ERb mRNA expression and the expression levels of miR-206 are gradually decreased as the score for ERa protein expression increases in breast cancer tissues. Moreover, transfection experiments revealed that introduction of miR-206 into estrogen-dependent MCF-7 cells inhibits cell growth and induces a dose-dependent repression of ERa mRNA levels. Transfection with miR-206 produces a dose-dependent decrease of mRNA expression of ERa-target genes, such as progesterone receptor, cyclin D1 and pS2 in MCF-7 cells. Our results suggest that miR-206 is a key factor for the regulation of ERa expression in development and progression of human breast cancer and could be a novel candidate for endocrine therapy that targets only ERa.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3042.
Insulin like growth factor in breast cancer subtypes.
Authors: Yerushalmi R , Gilks B , Nielsen T , Leang S , Cheang M , Woods R , Gelmon K , Kennecke H 
Published: December 2010

Abstract
Abstract #3048
Background: Insulin Like Growth Factor -1 Receptor (IGF-1R) is an important new therapeutic target expressed in all cancer types. IGF-1R supports cell survival pathways implicated in resistance to cancer therapy. Knowledge of the pattern of IGF-R1 expression among breast cancer subtypes and its impact on prognosis may enhance development of therapeutics targeting this pathway.&#x2028; Methods: Patients with early breast cancer cases, stage I-III, referred to the BC Cancer Agency from 1986 to 1992 were included. Archival paraffin tissue blocks were used to construct a tissue microarray. Among 4,046 patients with early stage on the TMA, 1,238 patients (30.6 %) were excluded due to missing subtype biomarkers, IGFR staining or both. Breast cancer subtypes were defined as Luminal A (ER/PR+, HER2- and Ki67 &lt;19%), Luminal B (ER/PR+,and HER2- and Ki67 &gt;19%), Luminal HER2+ (HER2+ and ER/PR+), HER2 (HER2+ and ER-and PR-), and Basal {HER2-,ER-PR- and (CK 5/6+ and/or EGFR+)}. IGF-1R staining was done with Santa Cruz antibody and was scored negative if there was no or weak staining and positive if staining was moderate or strong. Chi-square and Kaplan-Meier Survival analysis were done to compare IGF-1R expression among subtypes and determine impact on Breast Cancer Specific (BCSS) and Overall Survival (OS).&#x2028; Results: A total of 2,808 evaluable cases were included with a median follow-up of 12.5 years. IGF-1R staining was scored positive in 86.4%, and negative in 13.6%. Cases with Luminal A (1,676), Luminal B (426), Luminal HER2+ (199), HER2 (206 ) and Basal (301 ) had an IGF-1R+ rate of 89.9%, 94.4 %, 83.4%, 59.2% and 76.1%, respectively (p&lt;0.0001). 10 year BCSS was 68% (95% CI 66.0%-70.0%) in IGF-R1+ and 63% (95% CI 59.1%-66.9%) in IGF-R1 - group. Among subtypes, IGF-1R positivity was associated with improved BCSS only in Luminal A patients (p=0.015 ) and was not prognostic in other subtypes.&#x2028; Conclusion: Luminal breast cancer subtypes are associated with high rates of IGF1-R expression, while non-luminal groups have lower rates of expression. The prognostic impact of IGF-R1 expression supports the role of this pathway as a therapeutic target particularly among hormone receptor positive breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3048.
Associations between estrogen receptor (ER) Alpha expression levels and ER genotypes.
Authors: Henry NL , Shak S , Banerjee M , Skaar T , Palmer G , Braman M , Stearns V , Flockhart DA , Kleer C , Hayes DF , Rae J 
Published: December 2010

Abstract
Abstract #3049
Background: Estrogen receptors (ER) and associated factors, including progesterone receptors (PgR), modulate estrogenic effects both in normal tissue and in hormone receptor (HR)-positive breast cancers. ERα expression occurs in the majority of breast cancers, although the level of overexpression varies between tumors. Multiple single nucleotide polymorphisms (SNPs) in the genes that encode ER, termed ESR1 (ERα) and ESR2 (ERβ), have been shown to affect phenotypic outcomes, including breast cancer risk, bone mineral density, hot flashes, and lipid levels. We hypothesized that SNPs in genes that encode ER may affect level of ER overexpression.&#x2028; Methods: DNA was extracted from white blood cells from 100 subjects with HR-positive breast cancer enrolled in a tamoxifen observational study. SNPs in ESR1 (XbaI: rs#9340799, PvuII: rs#2234693) and ESR2 (01: rs#1256049; 02: rs#4986938) were determined from germline DNA using TaqMan. ER overexpression in paraffin-embedded formalin-fixed tumor specimens was quantified with immunohistochemistry (IHC) of tumor specimens on slides (Ventana Image Analysis System) and with RT-PCR using the Oncotype DX breast cancer assay (Genomic Health, Inc). Gene expression of other ER-associated genes (PgR, BCL2, and SCUBE2) was determined using RT-PCR (Oncotype DX). Expression of ER and associated genes across ER genotype was performed using the Kruskal-Wallis test. For all analyses, a p value of &lt;0.05 was considered statistically significant.&#x2028; Results: ER expression assessed using IHC and RT-PCR was statistically significantly correlated, with a Pearson correlation coefficient of 0.43 (p=0.0006). However, there was no association between the ESR1 or ESR2 genotypes and ER expression assessed by either method. A trend between ESR1 XbaI genotype and PgR expression by RT-PCR was noted (p=0.08 for gene-dose effect). No other associations between ER polymorphisms and expression of ER-related genes were identified.&#x2028; Conclusions: SNPs in genes encoding for ER do not appear to be associated with level of ER expression in breast cancer. Differences in ER expression between individual tumors are likely due to mechanisms other than these inherited mutations in the ER genes.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3049.
Estradiol downregulates miR-21 expression and miR-21 gene targets in MCF-7 breast cancer cells.
Authors: Wickramasinghe NS , Manavalan TT , Riggs KA , Li Y , Klinge CM 
Published: December 2010

Abstract
Abstract #3051
Select changes in microRNA (miRNA) expression correlate with diagnostic markers used in breast cancer therapies, e.g., estrogen receptor α (ERα) and tumor grade. However, no one has examined how estradiol (E2) regulates miRNA expression in breast cancer cells. Here miRNA microarrays were used to identify miRNA genes regulated by E2 in MCF-7 breast cancer cells. Twenty-five miRNAs were E2-regulated and select results were confirmed by quantitative-PCR. E2 reduced the expression of miR-21, an oncogene, and repression was inhibited by the antiestrogen ICI 182,780, ERα knockdown by siRNA, and by pre-treatment with Actinomycin D or cycloheximide. Thus, E2-ERα reduces miR-21 expression by primary transcriptional and secondary target activities. The effect of E2 on luciferase reporters containing the miRNA recognition elements (MREs) from the 3'-UTRs of 8 putative miR-21 regulated genes: CCM1, SKI, TGFB1, PDCD4, RAB6A, RAB6C, RASA1, and RASGRP1 was tested in MCF-7 cells. E2 increased luciferase with the MREs from TGFB1, PDCD4, RASA1, and RASGRP1, and from the full length 3' UTR of the PDCD4 gene, consistent with an E2-mediated decrease in miR-21 resulting in increased stability of Renilla mRNA and increased luciferase activity. Antisense to miR-21 increased luciferase from the TGFB1,PDCD4, RAB6A, and RASGRP1 reporters, consistent with these MREs being bona fide miR-21 targets. The E2-mediated decrease in miR-21 correlated with increased expression of miR-21-targets PDCD4, PTEN, and Bcl-2 at the protein level and these increases were blocked by AS to miR-21 and by siRNA knockdown of ERα. These results identify miR-21 as an ERα- regulated miRNA in MCF-7 cells.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3051.
Ixabepilone plus capecitabine vs capecitabine in patients with triple negative tumors: a pooled analysis of patients from two large phase III clinical studies.
Authors: Rugo HS , Roche H , Thomas E , Blackwell K , Chung H , Lerzo G , Volles LA , Poulart V , Perez E 
Published: December 2010

Abstract
Abstract #3057
Introduction: Patients (pts) with ER/PR/HER2 negative advanced breast cancer (triple negative, TN, basal-like) have limited treatment options and a poor prognosis. Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts either resistant to (study 046; JCO, 2007) or pretreated with anthracycline (A) and taxanes (T) (study 048). In 048, ixa + C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43 vs. 29%). A trend towards increased OS was seen in both 048 (HR 0.90 [0.78-1.03]) and 046 (HR 0.90 [0.77-1.05]), which did not reach statistical significance. Here we present a pooled analysis of efficacy endpoints (ORR, PFS and OS) in pts with TN disease from these 2 phase III studies.&#x2028; Methods: 1973 pts with MBC previously treated with A and T were randomized in 2 phase III trials (046 and 048) to receive either ixa (40 mg/m2 IV over 3h Q3w) + C (1000 mg/m2 PO BID x14d Q3w) or C alone (1250 mg/m2 PO BID x14d Q3w). Due to the similarity of the study populations, individual pt data from both studies was pooled to better evaluate treatment effect within pre-planned patient subgroups.&#x2028; Results: 443 pts had TN disease in the two studies combined. ORR and PFS were superior in pts receiving combination therapy compared to those on C alone with a trend towards improved survival that did not reach statistical significance.&#x2028; &#x2028; Conclusions: Ixa + C is the first combination to show statistically significant PFS benefit in pts with advanced TN breast cancer from a pooled analysis of 2 phase III trials. Clinical benefit was consistently seen pts with TN disease in the individual studies as well.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3057.
Activity and mechanism of action of histone deacetylase inhibitors in trastuzumab resistant breast cancer.
Authors: Radke S , Kumar A , Jones L , Tuck DP , Harris LN 
Published: December 2010

Abstract
Abstract #3060
Introduction: The Her2 antibody trastuzumab (T) is the first biological therapy that has proven the value of Her2 blockade in breast cancer. However, not all patients respond to trastuzumab and relapses occur after this treatment. Several studies suggest that histone deacetylase inhibitors (HDACis) are active in Her2-amplified breast cancer but none of them have addressed the role of HDACis in trastuzumab-resistant breast cancer. HDACis act by inhibiting the deacetylation of histones and other non-histone proteins such as Hsp90. Our goal is to study the activity, optimal sequencing and mechanism of action of HDACis in Her2-amplified cell lines, which demonstrate either de novo or acquired resistance to trastuzumab.&#x2028; Methods: T-sensitive and Her2-overexpressing BT474 & SkBr3, T-resistant BT474 and de novo T-resistant cell lines MDA-MB361, MDA-MB453, UACC812 and UACC893 were used for all experiments. The HDACi TSA (0-1uM) and trastuzumab at 100ug/mL were used for proliferation assays applying WST1 reagent (Roche). Western-immunoblotting was performed using cell lysates from untreated and treated cells. Proteolytic cleavage of caspase-3 and PARP was analyzed as indicator for apoptosis, Akt expression and phosphorylation for survival, Her2 and Erk1/2 expression and phosphorylation for proliferation and Hsp90 and Hsp70 were analyzed as key enzymes for chaperone activity.&#x2028; Results: TSA inhibited proliferation in all cell lines [IC50 100-300 nM]. The addition of trastuzumab was antagonistic in de novo T-resistant cell lines MDA MB 453, UACC 812 and 893 but did not change the effect induced by TSA in acquired T-resistant cells (BT474_H100). Her2 expression decreased in TSA and TSA+T treated cells but not in cells treated with trastuzumab alone. Erk1/2 phosphorylation decreased in TSA and TSA+T treated cells but was not affected by trastuzumab alone. Similar phosphorylation patterns were observed regarding Akt. Of note, Akt, Erk1/2, Hsp90 and Hsp70 levels did not change. Finally, TSA induced caspase-3 and PARP cleavage when given as single agent or in combination with trastuzumab.&#x2028; Discussion: This study suggests that HDACis are active in both trastuzumab-sensitive and de novo or acquired trastuzumab-resistant cell lines. However, use of trastuzumab together with TSA may be antagonistic in tumors that are resistant against trastuzumab. Further studies are required in these cell lines in order to elucidate the mechanism of resistance against trastuzumab and the mechanism of the here observed antagonistic effect between trastuzumab and TSA.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3060.