bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytotoxic doses of curcuminoids provoke a down-regulation of phospholipid biosynthesis – a focused metabolomic profiling.
Authors: Bayet-Robert M , Morvan D , Chollet P , Barthomeuf C 
Published: December 2010

Abstract
Abstract #6029
Background: Curcuminoids of which curcumin have proved efficacy in breast cancer prevention [Aggarwal et al, Anticancer Res (2003);23(1A):363]. In addition, there is growing evidence that these compounds may treat cancer [Karunagaran et al, Curr Cancer Drug Targets (2005);5(2):117]. However, the mechanisms of cytotoxicity of curcuminoids remain partially unknown. Functional genomics include several tools increasingly applied in pharmacology, like DNA and RNA microarrays, and proteomics. It was recently shown that a novel post-genomics technology, NMR spectroscopy-based metabolomics, was able to unravel metabolic pathways of the response to anticancer drugs [Morvan et al, Cancer Res. (2007);67(5):2150 ; Bayet-Robert et al, AACR Proceedings (2008);abstract 3938]. We applied this technique to investigate the metabolic features of the response of MCF7 human breast carcinoma cells to curcuminoids. We here report the analysis of the phospholipid metabolism subset of our data.&#x2028; Material and Methods: MCF7 cells were exposed to 10 µg/mL curcuminoids and followed at 12, 36 and 72 h intervals of time. Cytotoxicity assay was performed using Hoescht 33342. A novel high resolution magic angle spinning 1H-NMR spectroscopy-based metabolomics technique was used to obtain a quantitative metabolite profiling of about thirty metabolites, among which 8 phospholipid metabolism derivatives, in intact treated and untreated MCF7 cells.&#x2028; Results: A 72 h-exposure to 10 µg/mL curcuminoids decreased MCF7 cell survival to 4% (p=0.0039). Polyunsaturated fatty acids increased by +120% at 36 h and +62% at 72 h (both p=NS, Mann-Whitney test), phosphoethanolamine by +24% at 36 h (p=NS) and +120% at 72 h (p=0.0062), cytidinediphosphocholine (CDP-Cho) by +22% at 12 h, +132% at 36 h (both p=NS), and +547% at 72 h (p=0.0062). There was a decrease of phosphatidylcholine (PtdCho) by -30% at 36 h (p=NS), and -42% at 72 h (p=NS). Glycerophosphoethanolamine decreased by -28% at 12 h (p=0.0446) and glycerophosphocholine by -53% (p=0.0106). The PtdCho/CDP-Cho ratio decreased from +93% to +8% between 12 and 72 h, which indicates a blockade of PtdCho biosynthesis.&#x2028; Discussion and Conclusion: Our results are consistent with a rapidly progressive down-regulation of cholinephosphotransferase activity in response to curcuminoids, a biochemical mechanism closely linked to apoptosis [Miquel et al, J Biol Chem. (1998);273(40):26179 ; Cui et al, Biochim Biophys Acta. (2002);1585(2-3):87].
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6029.
Protein expression comparison and physiological profiling of matched pairs DCIS/normal and invasive/normal primary epithelial cells.
Authors: Minkeu A , Quong JN , Rosenberg A , Brill KL , Quong AA 
Published: December 2010

Abstract
Abstract #6031
Background: Approximately 50% of patients who are diagnosed with Ductal Carcinoma In-Situ (DCIS) develop invasive breast cancer. The progression from DCIS to invasive cancer is not well understood. To better understand the range of biological processes involved in this progression, we have successfully isolated primary epithelial cell cultures from patient breast tissue and are using mass spectrometry-based methods to identify differentially expressed proteins in these different cell types. Bioinformatics analysis was used to identify differences in the underlying pathways.&#x2028; Methods: Primary Human Mammary epithelial cells from DCIS and Stage 3 Invasive tumors and normal tissue from the same patient were isolated immediately after surgery. Cells were maintained in defined CNT27 media for up to 2 passages and were characterized for epithelial and breast cancer markers by immunohistochemistry and western blot. Tamoxifen response was measured by cell proliferation assay. Protein lysates were labeled with the ITRAQ isobaric tags. Two-dimensional high-pressure liquid chromatography and mass spectrometry were used to identify differentially expressed proteins.&#x2028; Results: The proliferation rate of cells from DCIS tissue was 33% higher than the matched control cells and 50% higher from invasive tissue. Furthermore, Tamoxifen was more effective at inhibiting DCIS cell proliferation than the invasive cells in a dose- and time-dependent manner. We identified 50-100 proteins differentially expressed between the different tissue types. Validated tumor markers such as members of protein S100 family were significantly different between the tumor and normal samples. Thrombospondin, a known angiogenesis inhibitor, had similar concentrations in normal and DCIS tissues but was down-regulated (ratio=0.4) in the invasive tumor samples.&#x2028; Discussion: Using the analogous methods from gene expression studies, we found that pathways associated with processes such as differentiation, angiogenesis, and invasion are enriched in the proteome of the invasive tumors. Further comparisons of additional samples is continuing with the goals of better understanding the underlying biology that drives DCIS to invasive breast cancer and ultimately defining markers that could be used in better prognosis for DCIS patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6031.
Uniformly positive (&gt;80%) HER2 expression maximizes sensitivity and specificity for prediction of response to trastuzumab in CALGB 9840.
Authors: Rimm DL , Broadwater G , Friedman P , Berry D , Seidman A , Hudis C , Winer E , Harris L , Thor A 
Published: December 2010

Abstract
Abstract #6046
Purpose: The recent ACO/CAP guidelines revised the cut-point for HER2 expression by immunohistochemistry (IHC) from 10% up to 30%. Recently we showed that heterogeneity of expression is a function of the assessed biomarker and, for HER2, &gt;80% area of expression was most prognostic and predictive. Here we test this hypothesis in CALGB 9840, a prospective cooperative group clinical trial of Paclitaxel (P) and Trastuzumab (T).&#x2028; Experimental Design: Tissue from 274 cases selected from cases with available slides from the TH arm were first scored by pathologists as 0-3+, but then again scored to assess percentage of tissue staining with prospectively chosen cut points of &gt;10%, &gt;30% or &gt;80%. Response was assessed by modified RECIST criteria, including complete and partial response. Stable disease and progressive disease were considered non-response.&#x2028; Results: Amongst the 176 cases treated with P+T there were 90 (52%) responses (PR+CR), 3 cases were unevaluable for response. In the subset of cases treated with T, there was inconsistent differences in the &gt;10% vs the &gt;30% categories but the &gt;80% category was uniformly statistically significantly predictive of response. Receiver Operator Characteristic (ROC) curves constructed to assess prediction of response showed areas under the curves (AUC) of 0.59 for IHC and 0.60 for FISH suggesting both are failed tests for defining an optimal cut-point. However, selecting only the cases scored as 3+ shows an AUC of 0.72 and the optimal cut-point is for the test is at 95% positive 3+ HER2 staining. This modification of the cut-point would have denied T to 6 of the 49 patients who responded to therapy in the 3+ group. However, there were also 41 (of 86) patients in the 0,1+ and 2+ groups that responded to therapy, raising the possibility that the response in those 6 patients may have been unrelated to T therapy.&#x2028; Conclusions: When using clinical outcome to assess the value of the current tests for prediction of response to T, ROC curves suggest that both the old and new HER2 tests fail at defining an optimal cut-point. However, using only strongly positive cases (3+), an acceptable test can be achieved which is maximized at 95% area of expression. This cut-point, while statistically rigorous, is limited by the fact that the patients were treated with both P and T. This result suggests a similar analysis is warranted on a larger cohort of T treated patients, perhaps in the adjuvant or neoadjuvant setting. The availability of other options for HER2 amplified cases (ie lapatinib) and the increased use of T in the adjuvant setting warrant optimization of tests for the best possible patient selection.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6046.
p53 mutational status, but not immunohistochemical staining (IHC), is associated with a clinical response of the primary tumor in women receiving neoadjuvant docetaxel-capecitabine chemotherapy for locally advanced breast cancer.
Authors: Ross JS , Perou CM , Aki N , Patten N , Wu L , McKenna EF , Lawrence H , Royce M , Avisar E , Gluck S 
Published: December 2010

Abstract
Abstract #6047
Background: The XeNa trial enrolled 157 patients in a multicenter Phase II study of neoadjuvant capecitabine and docetaxel in women with operable early stage breast cancer (T2-T3, N0-N1). HER2-positive patients also received trastuzumab. The primary endpoint was the rate of pathological complete response (pCR; residual cancer burden [RCB] = 0) and near-complete response (npCR; RCB = 1). A secondary endpoint of the study was to evaluate the association between p53 alterations and response to chemotherapy.&#x2028; Methods: p53 status was assessed in by mutational analysis on all cases using a microarray-based resequencing assay (AmpliChip p53 – Roche Molecular Systems, Pleasanton, CA); and also by IHC (using the Bp-53-11 antibody (CONFIRM™, Ventana, Tucson, AZ) in 120/157 (76%) of the cases. Gene expression profiling for breast cancer subtypes was also performed using a new 50-gene centroid-based method.&#x2028; Results: p53 mutations were detected in 78/157 (50%) of cases with 70% missense, 17% nonsense, 11% frame shift and 1% splice site. Silent mutations were rare (1%). Concordance of AmpliChip mutation status with IHC + staining was 65% (78/120 samples). Of the 16/60 (27%) cases which were IHC - and AmpliChip p53 mutation +, 10 (63%) had non-missense mutations which are typically IHC -. In the 60 mutation negative cases with IHC data, there were 26/60 (46%) IHC + cases. p53 mutation + status by AmpliChip was highest in Basal-like (75%) and HER2-enriched (57%) subtypes and lower in Luminal A (29%), Luminal B (12%) and Normal-like (39%). p53 IHC + staining varied little among the subtypes (35 to 50%) and did not correlate with p53 mutational status. The frequency of pCR and npCR was significantly higher in cases with p53 sequence mutations (20/58 - 35%) than in patients without mutations (7/52 - 13%; p = 0.014; 2-tailed Fisher's Exact Test), and this trend was apparent in both HER2+ and HER2- cases. IHC status did not correlate with treatment response (18% pCR and npCR in IHC- cases vs. 27% in IHC + cases; p = 0.35). Notably 3 cases achieving pCR had non-missense p53 mutations and were IHC -.&#x2028; Conclusion: P53 mutations were found in 50% of locally advanced breast cancers and were more frequent in Basal-like and HER2-enriched subtypes and less common in other subtypes. IHC staining lacks sensitivity and specificity for the presence of p53 mutations. In contrast to studies of anthracycline-based therapy, tumors harboring p53 mutations, especially missense mutations, respond better to this taxane-based regimen than wild-type tumors. P53 mutational analysis is a more accurate predictor of treatment response than IHC.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6047.
Comparison of MRI tumor volumetric and diameter measurements for predicting recurrence free survival in breast cancer patients undergoing preoperative chemotherapy.
Authors: Newitt DC , Gibbs J , Partridge SC , Li KL , Lobo EC , Esserman L , Hylton NM 
Published: December 2010

Abstract
Abstract #6053
Background: Assessment of tumor response to chemotherapy has traditionally relied on the bidimensional tumor measurement guidelines proposed by the World Health Organization (WHO, 1979) and more recently on the unidimensional Response Evaluation Criteria in Solid Tumors (RECIST, Therasse et al., 2000). MRI is being used increasingly to monitor breast cancer response to preoperative chemotherapy and allows both linear and volumetric assessment of tumor size. The purpose of this study was to compare pre- and post-treatment RECIST, WHO, and volumetric measures of tumor size on MRI for predicting recurrence free survival (RFS) in patients undergoing preoperative chemotherapy.&#x2028; Materials & Methods: 56 patients with locally advanced breast cancer were imaged with MRI (1.5T GE scanner) before and after 4 cycles of preoperative chemotherapy. Tumor longest diameter (LD) at physical exam (ClinLD) was recorded before (N=56) and after (N=48) treatment. Fat suppressed, contrast enhanced, T1-weighted sagittal 3DFGRE images (TE/TR=8/4.2ms, flip=20°, 2mm thick, 18-20cm FOV, 256x192 matrix) were acquired for tumor size measurements.&#x2028; All MRI LD measurements were made manually following RECIST and WHO guidelines. Tumor volume was measured with a semi-automated tumor segmentation algorithm based on a specific enhancement ratio calculation. Univariate Cox proportional hazards analysis was used to assess the value of clinical, pathology, RECIST, WHO, and volume measurements for predicting RFS. Variables with p&lt;0.15 were combined in a stepwise multivariate model to determine the greatest predictive value.&#x2028; Results: 23 patients have recurred since surgery (mean time 132 weeks). The mean RFS in the non-recurrent group is 330 weeks. Results for univariate and multivariate analysis are show in the Table. Final tumor volume was most predictive of recurrence free survival, and was the only variable found to be an independent significant predictor in the multivariate analysis. Age, tumor grade, and positive lymph node status were not significant predictors.&#x2028; Discussion: Post-chemotherapy tumor volume calculated via a semi-automatic algorithm was found to be a significant predictor of RFS for patients undergoing preoperative chemotherapy, out-performing manual 1D RECIST, 2D WHO, and clinical measurements. The results support previous work demonstrating the value of MRI tumor volume for predicting patient outcome.&#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6053.
Tumor tissue levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and survival following adjuvant chemotherapy in pre-menopausal lymph node-positive breast cancer patients (N=525).
Authors: Schrohl A , Look MP , Meijer-van Gelder ME , Foekens JA , Brünner N 
Published: December 2010

Abstract
Abstract #6054
Predictive markers are needed to guide planning of adjuvant therapy for breast cancer patients. We have recently shown that high tumor tissue levels of TIMP-1 are associated with decreased response to chemotherapy in metastatic breast cancer (Schrohl et al, Clin Cancer Res, 2006) suggesting that TIMP-1 may be a predictive marker in breast cancer patients.&#x2028; Purpose: This study investigates the association of tumor tissue TIMP-1 levels with response to adjuvant chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil) or an anthracycline-based regimen.&#x2028; Patients and Methods: 525 pre-menopausal lymph node-positive patients were included; 324 patients received adjuvant CMF, 99 received an adjuvant anthracycline-containing regimen and 102 had no adjuvant chemotherapy. Total TIMP-1 levels were measured using ELISA in cytosolic extracts of frozen primary tumors. Using the untreated patient group as a reference group we analyzed the benefit of adjuvant CMF and anthracyclines in TIMP-1 high and low patients, respectively. The median TIMP-1 concentration was used to dichotomize patients into high and low TIMP-1 groups. End points were disease-free and overall survival (DFS, OS).&#x2028; Results: The median TIMP-1 level in the total patient group was 12,54 ng/mg of total protein (range, 0 – 112,9 ng/mg). TIMP-1 levels in subgroups according to adjuvant therapy were not significantly different (P=0,20). In a multivariate model including basic clinico-pathological parameters, TIMP-1 low and high patients benefited differentially from adjuvant CMF and anthracyclines when compared to untreated patients. In particular, patients with high tumor levels of TIMP-1 had little benefit from adjuvant anthracyclines. Hazard ratios (HR) and 95% confidence intervals (CI) are given in the table for the analysis of DFS. A similar pattern was seen in the analyses of OS. In the CMF-treated group, both TIMP-1 low and high patients had significantly better survival than untreated patients (P&lt;0,01). Among anthracycline-treated patients those with TIMP-1 low tumors appeared to benefit more from the adjuvant therapy than TIMP-1 high patients although these results did not reach significance in the present analyses.&#x2028; &#x2028; Conclusion: This study suggests that high tumor tissue TIMP-1 levels are associated with decreased benefit from adjuvant chemotherapy. Especially in the group treated with anthracycline-based therapy there is a strong tendency for TIMP-1 high tumors to be less sensitive to the treatment. This group, however, is small and should be enlarged to confirm our results. In the group treated with CMF all patients benefit from the therapy with TIMP-1 high patients having slightly less benefit than TIMP-1 low patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6054.
CtIP, a BRCA1 binding protein, is a transcriptional corepressor of estrogen receptor α.
Authors: Ludes-Meyers JH , Wu M , Aldaz C 
Published: December 2010

Abstract
Abstract #606
The role of estrogen and estrogen receptor (ER) transcriptional regulation in breast carcinogenesis is indisputable. In the last few years there has been dramatic progress in understanding how receptor transcriptional coactivator and corepressor complexes operate.&#x2028; We demonstrated that CtIP (CtBP interacting protein) is downregulated in tamoxifen resistant breast cancer lines. Furthermore, CtIP protein expression correlates with response to neo-adjuvant endocrine therapy and patients with progressive disease express lower CtIP protein in their primary breast carcinomas than those who respond. CtIP expression directly correlates with ER alpha expression, and inversely correlates with disease free survival and breast cancer metastasis. Importantly, silencing endogenous CtIP confers tamoxifen resistance in tamoxifen sensitive breast cancer cells and re-expression restored tamoxifen sensitivity in resistant breast cancer cells (Wu et al. Molec. Cancer Res. 2007; 5: 1285-1295). Our findings indicate that CtIP silencing is a novel mechanism for the development of tamoxifen resistance in breast cancer.&#x2028; CtIP interacts with the BRCT domains of BRCA1 where most mutations occur in familial BRCA1 breast cancers. CtIP also interacts with the transcriptional corepressor CtBP. Emerging evidence suggests that CtIP is involved in transcriptional repression and may be a tumor suppressor gene. We hypothesize that CtIP plays a key role in repression of ER transcription and such repressive function is linked to the inhibitory growth effects exerted by tamoxifen. We further speculate that CtIP inhibition of ER transcription is mediated by its ability to bridge BRCA1 with CtBP to form a transcriptional corepressor complex able to modulate ER activity via the interaction between BRCA1 and ER and that CtIP is in fact required for BRCA1 to exert its transcriptional repression activity on ER. We will present our work showing that CtIP, BRCA1 and CtBP form a multiprotein complex, that requires CtIP, and associates with ER in breast cancer cells. More importantly, we will show that BRCA1, CtIP and CtBP associate with ER on the ER-dependent promoter of the pS2 gene in the absence of ligand. Stimulation by ligand leads to dissociation of the complex and ER-dependent gene expression. Furthermore, silencing CtIP expression using RNAi in E2-starved MCF-7 cells led to an increase of basal transcription of the pS2 gene. CtIP was also observed to repress E2 stimulation of ERE-luciferase in transfected MCF-7 cells. We are currently characterizing the role of the CtIP corepressor complex in ER-transcriptional activity. We will present the results of our efforts to identify specific ER-dependent promoters repressed by the CtIP corepressor. In addition, we will present results of studies aimed at characterizing CtIP-specific changes in chromatin remodeling and ER-cofactor recruitment at ER-dependent promoters.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 606.
p53 mutations to predict efficacy of alkylating-containing regimen: a metaanalysis of four different clinical trials.
Authors: Lehmann-Che J , André F , Desmedt C , Giacchetti S , Sotiriou C , Turpin E , Espié M , Marty M , Piccart M , Pusztai L , De Thé H 
Published: December 2010

Abstract
Abstract #6064
Background. The predictive value of p53 mutations for efficacy of anthracycline-based chemotherapy is matter of controversy. Inconsistencies among studies could be related to the heterogeneous use of alkylating agents in combination with anthracyclines in different studies. We examined the predictive value of p53 mutations in four different series of breast cancer patients treated with preoperative anthracycline-based chemotherapy including different doses of cyclophosphamide (C).&#x2028; Patients and Methods. All patients had stage II-III breast cancer and received anthracycline-containing chemotherapies. A total of 352 patients were included in four different clinical studies : 65 patients with estrogen receptor (ER)-negative cancers treated with single agent epirubicine (E) (100 mg/m2/3w x 4) in the TOP trial (R1), 52 patients treated with FAC (500 mg/m2 C, 5-FU and 50 mg/m2 doxorubicin/3w x 6) (R2), 96 patients treated with EC-T (75mg/m2 E and 750 mg/m2 C/3w x 4 followed by 100mg/m2 docetaxel/3w x 4) (R3) and 139 patients treated with dose-dense EC (1200mg/m2 C and 75 mg/m2 E/2w x 6) (R4). Before therapy, p53 status was determined in all tumors by yeast functional complementation (FASAY) assay. After chemotherapy, all patients underwent surgery. Pathologic complete response (pCR) was defined as no residual invasive tumour cells in breast and lymph nodes.&#x2028; Results. P53 mutations were more frequently observed in the 128 ER-neg compared to ER-pos cancers (78% vs 29.4%). In p53 mutated tumours, the pCR rate increased with the dose-intensity of C. Conversely, in p53 wild type tumours, pCR rates decreased.&#x2028; &#x2028; Focusing on ER-neg, p53 mutated tumors, the pCR rates rose from 11%, 6%, 32% to 52% in R1, R2, R3 and R4 groups. The R1 and R4 regimen, differing only in C dose intensity, showed marked differences in pCR in ERneg tumors.&#x2028; &#x2028; Conclusions: Increasing doses of C do not seem to improve pCR rates in P53 wild type tumours, raising the possibility of antagonism with anthracycline in this group. On the other hand, in ER-neg, p53 mutant tumors, inclusion of dose-intense C seems to significantly increase pCR rates.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6064.