bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequential FEC 100-Docetaxel (T) Neoadjuvant Chemotherapy (NCT) in Stage II-III Operable Breast Cancer.
Authors: Dubray P. , Dubray P. , Abrial C. , Abrial C. , Mouret-Reynier M. , Mouret-Reynier M. , Nayl B. , Nayl B. , Thivat E. , Thivat E. , Gimbergues P. , Achard J. , Penault-Llorca F. , Penault-Llorca F. , Chollet P. , Chollet P. , Chollet P. , Chollet P. , Durando X. , Durando X. , Durando X. 
Published: December 2010

Abstract
Background: NCT is increasingly used for operable breast cancer to allow breast conservation. Our objective was to evaluate clinical and pathological response after sequential NCT of 3 cycles of FEC 100- 3 cycles of T. This chemotherapy is currently the reference in the adjuvant setting in France.In PACS 01 trial (Roche et al. J Clin Oncol, 2006) FEC followed by T significantly improved 5 years overall survival rates (90.7%) compared to 6 FEC 100 in node-positive breast cancer. However this active combination has not yet been evaluated in NCT.Methods: 101 patients (pts) from February 2005 to September 2008 with pathologically confirmed stage II-III untreated operable breast cancer received 3 cycles (c) of FEC 100 (epirubicin 100 mg/m² + 5-fluorouracil and cyclophosphamide 500mg/m²) followed by 3 c of T (100mg/m²) every 3 weeks. pCR was defined according to Chevallier's (Am J Clin Oncol, 1993) as level 1 and 2 and to Sataloff's classification (J Am Coll Surg, 1995) as grade A. A clinical, mammography and ultrasound breast evaluation was performed at baseline, after 3 c and before surgery.Results: Median age was 52.3 years [28-72]. Median diameter of the tumor was 42 mm [14-100]. 83 pts had a ductal, 14 a lobular, 3 ductal and lobular, 1 another carcinoma. 8.9% were grade I SBR, 58.4% grade II SBR, 28.7% grade III SBR and 4% unspecified. 74 (73.3%) tumors were HR+, 9(8.9%) Her-2 + and 18(17.8%) triple negative. 55 pts (54.4%) were premenopausal.After 3 cycles of FEC 100, ultrasound objective response rate (ORR) was 15%: 13 pts had a partial response and 2 pts had a complete response.After 6 cycles of NCT, ultrasound ORR was 62.5%: 53 pts had a partial response and 7 pts had a complete response.Most frequent grade (G) 3-4 adverse events were neutropenia which occured in 16 pts (15.8%) with G 3 febrile neutropenia in 11 pts (10.9%) (G-CSF optional). Most frequent G 1-2 averse events were nausea which occured in 43 pts(42.6%), myalgia in 27 pts(26.7%) and stomatitis in 23 pts(22.8%).After the completion of NCT, 76 pts (75.2%) underwent breast-conserving surgery. 12(11.9%) achieved pCR using Chevallier's classification and 15(14.8%) using Sataloff's classification.Conclusion: Sequential NCT with FEC followed by T was active and relatively well tolerated. Breast-conserving rate appeared satisfactory.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1105.
Breast Cancer Patients Receiving Neoadjuvant, Adjuvant and Palliative Chemotherapy Have Different DNA Oxidative Damage and Repair Profiles.
Authors: Laura V. , MCarmen R. , Pedro S. , Cesar R. , Sergio G. , Jose L. , Jose Q. 
Published: December 2010

Abstract
Background: Antineoplastic agents induce oxidative stress in biological systems leading to lipid, carbohydrate, protein and DNA damage and affecting cell structure and function. These adverse effects may fuel up the acquisition of new mutations and the development of treatment resistances and secondary malignancies.Methods: We selected 90 breast cancer patients receiving neoadjuvant, adjuvant or palliative chemotherapy, to test the effect of this treatment on the systemic oxidative stress. The patients were distributed in equal groups and paired blood samples, before and after chemotherapy, were extracted. DNA oxidative damage was assessed by alkaline comet assay and a specific inmnoenzymoassay was employed to determine RPA and Ku86 DNA repair activity.Results: We found that neoadjuvant patients presented a marked raise in DNA damage after chemotherapy (Figure 1A). DNA repair activity of KU86 was significantly higher in the adjuvant setting and significantly lower in the neoadjuvant and metastatic settings after chemotherapy. Before chemotherapy administration, KU86 activity was higher in the metastatic and neoadjuvant groups compared to the adjuvant group (Figure 1B).Discussion: Our results show that chemotherapy induces the production of free radicals to an extent that causes a severe DNA damage. High levels of DNA damage are maintained along successive clinical interventions, due to continued production of free radicals during breast cancer treatment, despite the activation of the repair mechanisms that are not sufficient to overcome the effects of the oxidative stress at this level. Our work shows that breast cancer treatment affects the redox status of the patients and, because of its effects into cellular signaling pathways and gene expression, it must be considered as a potential therapeutic target to improve breast cancer treatment and minimize the associated toxicity.Figure legend 1.- Oxidative DNA damage and DNA repair markers in neoadjuvant, adjuvant and metastatic patients, before and after chemotherapy. (A) Percentage of DNA in the tail of lymphocytes, as measured by comet assay. (B) DNA repair activity of KU86. Intragroup statistical differences owed to chemotherapy are indicated as ‡ (P&lt;0.001) or * (P&lt;0.05). Intergroup statistical differences for each period (before and after chemotherapy) (P&lt;0.05) are indicated by the letters a and b, in such a way that the measures with different superscript letters, are statistically different.Figure legend 2.- Fluorescent microscope images of damaged lymphocytes from a neoadjuvant patient before (A) and after (B) chemotherapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1123.
miR-206 Expression Is Downregulated in Cyclin D1 Amplified Breast Tumours.
Authors: Ahnström Waltersson M. , Karlsson E. , Nordenskjöld B. , Fornander T. , Skoog L. , Stål O. 
Published: December 2010

Abstract
Amplification in the 11q13 region has been found in around 15% of all breast cancers and is strongly correlated with oestrogen receptor (ER) positive tumours. We have previously found that amplification of at least one of the genes PAK1 or CCND1 is associated with decreased recurrence-free survival among ER+ patients. Other genes in the amplicon might also contribute to this effect and situated close to CCND1 are the FGF-3, -4 and -19 genes. The FGF-4 protein has been shown to inhibit the expression of the ER a regulator miR-206 in chicken embryo. In this study we analysed 23 tumours with and 27 tumours without previously detected 11q13 amplification to explore if 11q13 amplification is associated with decreased levels of miR-206 and if miR-206 is associated with ER expression. Using eal-time PCR, we found that miR-206 expression was inversely correlated to CCND1 and 11q13 amplification (P=0.016 and P=0.022 respectively). Tumours with low miR-206 expression had higher levels of ER a than tumours with intermediate and high expression (P=0.043). In vitro studies of the breast cancer cell lines SKBR3 and ZR751 showed that treatment with FGF-3, -4 or -19 lowered the expression of miR-206. We conclude that miR-206 might be an important regulator of ER a expression. Our results that low mir-206 is associated with CCND1 amplification and thereby also FGF-4 amplification in combination with the findings that FGF-3, -4, and -19 may regulate the expression of miR-206 in vitro points towards the possibility of a miR-206 regulator, FGF-4 or another FGF, present in the amplicon.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1127.
A Functional Role for CERT in Cancer Drug Induced Autophagy and Prognosis in Her2 Positive Breast Cancer.
Authors: Lee A. , East P. , Nicke B. , Jones N. , Downward J. , Gorman P. , Roylance R. , Murphy N. , Hanby A. , Swanton C. , Swanton C. 
Published: December 2010

Abstract
CERT was recently identified in a functional genomic siRNA screen for regulators of multi-drug sensitivity. CERT encodes a ceramide transporter which shuttles the pro-apoptotic lipid ceramide from the endoplasmic reticulum to the golgi. Silencing CERT, promoted sensitivity to paclitaxel, doxorubicin, cisplatin and 5-FU in breast, colon and non-small cell lung cancer cell lines. Further analysis of CERT expression in 18 NCI-60 cancer cell lines together with drug sensitivity data for over 5000 drugs within the NCI database, revealed that elevated CERT expression is associated with multi-drug resistance to diverse cancer cytotoxics. CERT mRNA was significantly elevated in HER2 positive breast cancer cell lines. Consistent with these data, in a primary breast cancer tissue microarray cohort of 356 primary breast cancers with outcome data, CERT protein expression was significantly greater in Her2 positive disease (p&lt;0.0001). Survival analysis indicates that increased CERT expression correlates with significantly poorer long-term survival across the whole cohort and in Her2 positive patients.In order to explore the downstream molecular targets of CERT activity, we used the Affymetrix GeneChip Exon Array to detect gene expression changes following siRNA mediated CERT silencing. Genes that were differentially expressed following CERT silencing were identified and validated by real-time PCR. Significant representation of genes involved in the autophagy pathway were identified. One of these genes, LAMP2, a protein involved in autophagosome-lysosome fusion, is up-regulated following CERT silencing. LAMP2 silencing promotes paclitaxel resistance when depleted from cancer cells. Consistent with a role for CERT silencing in mediating an autophagy response following drug exposure, CERT depletion together with Paclitaxel treatment induces alterations in the autophagy response marker-LC3 similar to those seen in starvation-induced autophagy and an increase in lysosomal activity as visualised by microscopy. These data indicate a role for autophagy in regulating cytotoxic drug response in cancer.The pharmacological targeting of CERT, a poor prognostic marker in breast cancer, may be a rational approach to enhance drug response and patient outcome.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1137.
Tau Expression and Efficacy of Paclitaxel Treatment in Metastatic Breast Cancer.
Authors: Tanaka S. , Nohara T. , Iwamoto M. , Sumiyoshi K. , Kimura K. , Takahashi Y. , Tanigawa N. 
Published: December 2010

Abstract
Purpose: Paclitaxel is widely used for the treatment of patients with metastatic breast cancer (MBC), such as in anthracycline-based combinations as a first-line chemotherapy. Although several mechanisms of paclitaxel resistance have been demonstrated, useful markers of paclitaxel resistance have not been available in clinical practice. A recent study revealed that low tau expression in cases of early breast cancer can predict susceptibility to paclitaxel administration in neoadjuvant therapy.Methods: In this study, the clinical significance of tau expression in MBC cases was established by identifying candidates with paclitaxel administration. Tissue specimens obtained from 35 patients who had received neither chemotherapy nor radiotherapy before surgery were examined. Status of tau expression was determined by immunohistochemistry.Results: Based on a previously reported classification scheme, 15 cases were classified as tau-negative (0, 1+) and 20 cases were classified as tau-positive (2+, 3+).Nine (60%) of 15 cases with tau-negative expression showed favorable response. Conversely, 17 (85%) of 20 cases with tau-positive expression showed progressive or stable disease after paclitaxel administration.Table 1 Relationship between tau expression and response to paclitaxel nNumber of responses (%)PTaunegative159 (60%) positive203 (15%)0.01 Time to disease progression in tau-negative and tau-positive groups was 9.4 ± 6.6 months and 6.0 ± 3.7 months, respectively. Although no significant differences were apparent, this period tended to be longer in the tau-negative group.Discussion: Patients with tau-positive expression may derive less benefit than tau-negative from paclitaxel therapy in MBC. This suggests that tau expression could be used at diagnosis to select patients for whom paclitaxel treatment is likely to be of most benefit. However, this study has some clear limitations in terms of the modest sample size and the heterogeneity of eligible patients (e.g., different numbers and regimens for adjuvant and MBC chemotherapy). Many more cases must be examined before tau expression can be applied to practical clinical treatment.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1138.
Knockout of Heregulin (HRG) Expression Reverts Paclitaxel-Resistance and Promotes Mesenchymal Epithelial Transition (MET) of Triple Negative Breast Cancer Cells.
Authors: Li J. , Espinoza I. , Lupu R. 
Published: December 2010

Abstract
The growth factor Heregulin (HRG) is expressed in about 30% of breast cancer tumors, and induces tumorigenicity and metastasis of breast cancer cells. We have demonstrated previously that HRG overexpression renders breast cancer cells resistance to the microtubule-interfering agent Taxol, a drug of choice for the treatment of metastatic breast cancer. The mechanism by which HRG induces Taxol resistance is largely unknown. It is also known that triple negative breast cancer tumors do express high levels of HRG and unfortunately they do not respond to HRG. Our studies were aimed at targeting HRG with the goal of achieving a therapeutic target as well as restoring the response to Taxol, while preventing the formation of metastasis. Thus, we knocked-down HRG expression in three different breast cancer cell lines: MDA-MB-23, HS578T and BT549. Our data demonstrates that HRG expression is an absolute requirement for the anchorage-independent growth for triple negative breast cancer cells, since none of the breast cancer cells MDA-MB-231, HS578T and BT549 stable expressing the silencing (shRNA) for HRG, were capable of forming colony in soft agar. Furthermore, these cells, not only no longer were not anchorage-independent were no longer resistant to Taxol, to the contrary the shRNA/HRG cells were exquisitely sensitive to Taxol, to induce growth inhibition and apoptosis. More importantly, we observed that the disorganized structured observed in 3D matrigel culture observed for triple negative cells, was completely abolished once HRG was knockdown and a very organized structure. These characteristics resembled an EMT (epithelial-mesenchymal epithelial transition (MET). This should be deemed a potential target in developing therapies for triple negative breast carcinomas.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1142.
Epigenetic Control of Estrogen Synthesis in Human Preadipocytes and Breast Cancer Cells.
Authors: Knower K. , To S. , To S. , Simpson E. , Simpson E. , Clyne C. , Clyne C. 
Published: December 2010

Abstract
Estrogen plays a significant role in the development and progression of breast cancer (BC). Cytochrome aromatase p450, encoded by the gene CYP19, is the key enzyme catalyzing the synthesis of estrogens from androgens. In post-menopausal women, adipose tissue becomes the major site for estrogen production and an increase in CYP19 expression in mammary adipose is strongly linked to the hormone-dependent progression of BC. Therefore, understanding CYP19 regulation in BC is critical for the development of therapeutic measures. Previous studies of CYP19 regulation in BC have mainly focussed on hormone-induced regulation of transcription via upstream tissue- and promoter-specific regulatory regions. While this is clearly important, it is increasingly evident that epigenetic regulation of expression, such as DNA methylation, is also a common factor in the progression of cancers. The aim of this study was to investigate whether CYP19 expression is under epigenetic regulation and to determine if such mechanisms contribute to the tissue- and promoter-specific expression of CYP19 observed in BC.CYP19 transcripts in cancer-free primary human breast adipose fibroblasts (BAFs) stimulated with cytokines and glucocorticoids (e.g. TNFα and dexamethasone) are derived from the distal promoter 1.4, whereas breast tumour-derived factors (e.g. prostaglandin E2) induce a regulatory switch to proximal promoters 1.3 and II. DNA from BAFs maintained under these two conditions was treated with sodium bisulfite allowing for methylation analysis of CpG dinucleotides. Methylation mapping revealed a stochastic heterogeneous level of methylation among 9 CpG sites (promoter 1.4) and 11 CpG sites (promoters 1.3 and II) in untreated BAFs.No correlation was observed between promoter methylation and promoter activation after response to stimuli. However, treatment of BAFs with 5-aza-2'-deoxycytidine, a DNA methylation inhibitor, increased total CYP19 mRNA expression up to 40-fold, primarily via promoter 1.4 thorugh up-regulation of trans-acting factors, suggesting CYP19 is under tonic inhibition by methylation in BAFs. Similar results were also obtained in four BC cell lines. Ongoing work has elucidated trans-acting factors of CYP19 epigenetically silenced in BAFs. These studies uncover a new layer of complexity in the regulation of aromatase expression in BC and may identify new targets for epigenetic therapy, including DNA methylation inhibitors. These findings will translate to BC by determining the methylation state of CYP19 in clinical BC specimens, and by correlation with clinicopathological parameters such as steroid receptor status, grade and stage.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1147.
Epigenetics Differences between Estrogen Receptor (ERS1) and Her2/Neu Status in Breast Cancer Patients.
Authors: Martínez-Galán J. , Torres-Torres B. , Ales I. , Durán G. , Gutierrez V. , Del Moral R. , Cobo M. , Nuñez M. , Benavides M. , Ruiz De Almodóvar M. 
Published: December 2010

Abstract
Background: The CpG island methylator phenotype is associated with distinct clinicophatological characteristics as Estrogen Receptor (ESR1) positive and amplification of HER2 in breast cancer.Objetive: To evaluate epigenetics differences in tumor-related genes to ERS1 and HER2/neu status in primary breast cancer.Material and Methods: We quantified methylation levels of promoter of 5 genes (ERS1, RAR- β, 14-3-3 sigma, APC, E-Cadherin) which are to confer growth adventage to cells, in 107 women with breast cancer and 108 control subjects. Real Time QMS-PCR SYBR green (methylation-specific PCR) was used to analyze the hypermethylation. Tumours were classified as phenotype basal, luminal A, Luminal B and phenotype HER2+.Results: Ours analyses revealed low or absent methylation ESR1and 14-3-3σ in healthy controls and significant differences between breast cancer patients (pts) and healthy controls in relative serum levels of methylated gene promoters ESR1 (p=0.0112) and 14-3-3s (p=0.0047). Presence of methylated ESR1 in serum of breast cancer patients was associated with ER-negative phenotype (p=0.0179). Of the available cases, 60 pts (56%) were Luminal A, 10 pts (9.3%) Luminal B, 13 pts (12%) Basal like and 9 pts (8.4%) HER2+. We observed that methylated ERS1 was preferably associated with phenotype Basal Like and worse interval progression free and survival global though p&gt;0.05 and the amplification HER2+ was correlation with significant more frequent methylation gene (p&lt;0.05). Thet hypermethylation of normal ERS1 and 14-3-3σ combined differentiated between breast cancer patients and healthy controls (p=0.0001) with a sensitivity of 81% (95% CI: 72–88%) and specificity of 88% (95% CI: 78–94%).Conclusions: This study identifies the presence of variations in global levels of methylation promoters genes in healthy controls and breast cancer with different phenotype classes and shows that these differences have clinical significance. These showed that frequent methylation had a strong association with molecular phenotype of breast cancer and perhaps in the future can explain therapy resistance related to RE and HER2/neu status in breast cancer patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1151.
Critical Role of a Transcription Elongation Regulator in Mammary Gland Development and Mammary Tumorigenesis.
Authors: Nair S. , Li R. 
Published: December 2010

Abstract
For a long time transcriptional regulation was thought to primarily regulated at the stage of transcription initiation. However, recent genome-wide studies suggest that the majority of genes, both active and inactive, in human cells experience transcription initiation and many of them have RNA polymerase II (RNAPII) physically present at the promoter-proximal region. Thus, transcription elongation may represent a common but under-explored step for mammalian gene regulation. Cofactor of BRCA1 (COBRA1), which was first identified as a BRCA1-binding protein, acts as an integral subunit of the negative elongation factor (NELF) complex to stall RNAPII at the promoter proximal regions of multiple estrogen-responsive genes. COBRA1/NELF-B also shares a number of target genes for transcriptional regulation with BRCA1 in breast cancer cells. In support of its potential role in tumor suppression, its reduced expression is strongly correlated with metastatic breast cancer and knockdown of COBRA1 leads to elevated hormone-dependent transcription and accelerated cell proliferation both in vitro and in xenograft models.In order to get a better understanding of the molecular functions of Cobra1 in mammary gland, we employed Cre-lox system to delete mouse Cobra1 in the mammary gland. These mammary gland-specific Cobra1 knockout mice exhibit severe defects in alveologenesis and lactogenesis. These animals also show abnormal epithelial morphology specifically in the luminal compartment. Luminal epithelial population isolated from these mice using cell surface markers showed reduced colony forming ability both in 2-D and 3-D cultures. Molecular basis for the Cobra1-associated developmental defects and the possible impact of Cobra1 deletion on mammary tumorigenesis will be discussed. By linking regulation of transcription elongation with mammary gland-specific functions, our work establishes a new mode of gene regulation in mammary gland development.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1152.