bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-06-23: KLF8 Is Regulated by Its Novel Interacting Protein PARP-1
Authors: Lu H , Wang X , Urvalek AM , Li T , Yu L , Zhu J , Lin Q , Zhao J. 
Published: April 2011

Abstract
Krüppel-like factor 8 (KLF8) plays an important role in the progression of breast cancer invasion and metastasis. Using mass spectrometry and co-immunoprecipitation, we identified PARP-1, a chromatin-associated enzyme that catalyzes protein poly(ADP-ribosyl)ation (PARylation), as a novel KLF8 interacting protein. Co-IP and western blotting indicated that KLF8 is a PARylation substrate. Mutation of the cystein residues in the first and second zinc-finger motifs of KLF8 abolishes its interaction with PARP-1. Luciferase assays showed KLF8 activation on the cyclin D1 promoter was significantly reduced when PARP-1 was physically deleted or functionally inhibited or when KLF8-PARP-1 interaction was disrupted. Surprisingly, immunofluorescent staining demonstrated that KLF8 was localized in the nuclei of wide type MEFs, but was mislocalized in the perinuclear cytoplasm of the PARP-1-/- cells, which could be rescued by re-expression of PARP-1. The detection of γH2A.X, comet assay and clonogenic assay indicated KLF8 play a DNA repair role in a PARP-1- dependent matter. Cychloheximade-chase assay revealed the stability of KLF8 dramatically reduced by loss of PARP-1 or when KLF8-PARP-1 interaction was disrupted, meanwhile ubiquitination assay showed heavier ubiquitin chains of KLF8. This work has identified PARP-1 as a novel binding partner and post-translational modifier of KLF8 and a critical regulator of KLF8 localization, functions and stability in the cells and suggested a critical role of the interaction between KLF8 and PARP1 during metastatic progression of breast cancer. Support by: NIH, ACS and Komen grants to J.Z.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-23.
Abstract P4-06-24: KLF8 Induction of Mammary Epithelial Stem Cell Formation and Tumorigenesis by Regulating EMT-Associated MicroRNAs
Authors: Wang X , Lu H , Li T , Urvalek AM , Yu L , Bennett JA , Zhao J. 
Published: April 2011

Abstract
Although it is well established that the epithelial-mesenchymal transition (EMT) generates cells with properties of stem cells, the molecularmechanisms responsible for this change remain largely undefined. We set out to identify the mechanisms by examining the expression of stem cell markers as well as microRNAs in MCF-10A cells during EMT induction. By immunostaining and FACS analysis, we found that during EMT induction by either TGF-β treatment or overexpression of KLF8, both the expression of CD44high/CD24low and the activity of aldehyde dehydrogenase (ALDH) were dramatically increased. Using microRNA PCR array, we identified a microRNA signature associated with the EMT. Using microRNA inhibitor, We further demonstrated that one of the microRNAs, miR-146a, is upregulated and plays an important role in keeping the stem cell percentage during EMT induced by both TGF-β and KLF8, as revealed by manipulation of miR-146a expression, analysis of the stem cell markers and mammosphere growth. Taken together, these results highlight a novel role for miR-146a in regulating the stem-like cell induction from MCF-10A cells by EMT. Experiments are in progress to investigate the contribution of KLF8-regulated expression of miR146a and its targets to the stem cell induction and transformation. Supported by: NIH, ACS, Komen and NYSTEM grants to J.Z.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-24.
Abstract P4-07-10: Prognostic Significance of Triple Negative Breast Cancer at Tumor Size 1 Cm and Smaller
Authors: Lai H-W , Kuo S-J , Chi C-W , Chen S-T , Chang T-W , Chen D-R. 
Published: April 2011

Abstract
Triple negative breast cancer (TNBC) is an independent biomarker of poor prognosis, and associated with a higher predilection for visceral metastasis and early recurrence. However, the prognostic significance of TNBC with a tumor size ≥1 cm is unclear. Patients with primary operable breast cancer with a tumor size ≥1cm were retrospectively collected at Changhua Christian Hospital and National Cheng-Kung University Hospital in Taiwan. Tumors negative for ER, PR, and HER-2, determined by immunohistochemical stain, were classified as TNBCs and compared with tumors with any receptor positivity (non-TNBC) for disease-free survival (DFS) and cancer-specific survival (CSS). From 1995 to 2006, a total of 377 (13%) patients with tumor size ≥1 cm were enrolled from 2835 primary breast cancer patients. The mean age at diagnosis and follow-up time were 50.86 and 4.04 ± 2.83 years, separately. Compared with non-TNBC patients, TNBC with a tumor size ≥1 cm as a whole or in lymph node-positive subgroup was not associated with a poorer 5-year DFS and CSS. In lymph node-negative patients (pT1a-bN0M0), TNBC was associated with a poorer 5-year CSS but not DFS than the non-TNBC group. In multivariate Cox regression hazard analysis, lymph node invasion was the most important cause (hazard ratio: 19.89, 95% CI: 2.18-181.89, P=0.0081) of cancer-specific death.
Fig. (a) Disease-free survival (DFS) of TNBC patients versus non-TNBC patients with tumor ≥1 cm. (b) Cancer-specific survival (CSS) of TNBC patients versus non-TNBC patients with tumor ≥1 cm. (c) CSS in node-positive patients with a TNBC versus non-TNBC phenotype. (d) CSS in node-negative patients with TNBC versus non-TNBC. (e) DFS in patients with HR+/ERBB2-, ERBB2+, and TNBC. (f) CSS in patients of HR+/ERBB2- , ERBB2+, and TNBC. (g) CSS in node-positive patients with HR+/ERBB2-, ERBB2+, and TNBC. (h) CSS in node-negative patients with HR+/ERBB2- , ERBB2+, and TNBC.
TNBC is very likely an independent risk factor for CSS in small (≥1 cm) node-negative invasive breast cancer. With tumors 1 cm and smaller, lymph node invasion was the single most important prognostic factor.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-07-10.
Abstract P4-08-08: Cross Reactivity of Clinically Validated Anti-HER2 Antibodies
Authors: Schrohl A-S , Jensen SS , Pedersen HC , Nielsen SL , Brunner N. 
Published: April 2011

Abstract
Background: Human epidermal growth factor receptor (HER-) 2 belongs to the family of epidermal growth factor receptors (EGFRs) with homology to HER1, HER3 and HER4. HER2 is over-expressed in approximately 20% of invasive human breast cancers (Wolff, Hammond et al. 2007). Over-expression of HER2 is associated with a poor prognosis; however, the protein can be targeted by anti-HER2 therapy (trastuzumab, Herceptin®) (Slamon, Leyland-Jones et al. 2001). Trastuzumab therapy is offered only to patients whose tumors over-express HER2 protein and/or show amplification of the HER2 gene. Accordingly, the expression level of HER2 protein and/or amplification of the HER2 gene are determined routinely in all newly diagnosed breast cancers. Essential to this testing of HER2 expression at the protein level is the availability of specific antibody-based test systems.
Aim: The aim of the present study was to investigate the specificity of three clinically approved commercially available anti-HER2 antibodies towards members of the EGFR-family.
Methods: We studied the antibody used in the Herceptest™ (Dako), the PATHWAY® antibody (Ventana Medical Systems, Inc.) and the Oracle™ antibody (Leica Microsystems). Antibody specificity was investigated by manually performed immunohistochemistry (IHC) and in competitive ELISAs. For IHC, Chinese Hamster Ovary (CHO) cells were transiently transfected with the intracellular domain of respectively HER1, HER2, HER3 and HER4 and all three antibodies were applied to sections of formalin-fixed paraffin-embedded (FFPE) transfected cells. In ELISA, cross reactivity towards HER1 and HER4 was tested with peptides corresponding to the C-terminal part of HER1 and HER4.
Results: In IHC experiments, all three antibodies stained cells transfected with HER2. Binding of the antibodies to HER2 was confirmed bycompetitive ELISA. However, in IHC experiments the PATHWAY® and the Oracle™ antibodies also stained cells transfected with HER4. Competitive ELISAs confirmed binding of the PATHWAY® antibody to HER4, whereas binding of the Oracle™ antibody to HER4 could not be confirmed in a competitive ELISA. None of the antibodies cross reacted with HER1 and HER3 homologous to the HER2 binding site of the antibodies.
Conclusions: Two out of three clinically validated anti-HER2 antibodies were shown to cross react with HER4 in FFPE cells. As determination of HER2 over-expression and/or amplification guides therapy with trastuzumab, a valid test result by the use of specific antibodies is crucial to ensure proper personalized therapy with HER2-targeted therapy. These results warrant further investigation of anti-HER2 antibodies and of the procedures for clinical determination of HER2 protein expression. References:
Slamon DJ et al. (2001) J Med 344:783 Wolff AC et al. (2007) J Clin Oncol 25:118
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-08.
Abstract P4-08-09: The Prognostic Importance of “Detection Mode” and “Palpability” in Primary Operable Grade 2 Breast Cancers
Authors: Van Calster B , Zhang X , Vandorpe T , Van Limbergen E , Dieudonné A-S , Leunen K , Smeets A , Amant F , Berteloot P , Weltens C , Janssen H , Peeters S , Wildiers H , Paridaens R , Van Ongeval C , Van Steen A , Vergote I , Moerman P , Christiaens MR , Neven P. 
Published: April 2011

Abstract
Background: Histologic grade 2 breast cancer may benefit most from molecular classification for prognosis. We studied the prognostic value of ‘detection mode’ and ‘palpability’ together with other prognostic variables in a consecutive series of grade 2 lesions.
Patients and methods: We used follow-up data from new diagnosed and primary operable grade 2 breast cancers from UH Leuven (January 2000 - May 2005). Endocrine, chemo-and radiotherapy were given when indicated. The first appearing breast cancer related event (BCRE) was calculated as local (local, regional or contra-lateral) or metastatic (metastatic if both appeared together). These prognostic variables were assessed: age at diagnosis (per decade increase), tumor size (per cm increase), screening (yes/no), palpability (yes/no), lobular type (yes/no), chemotherapy (yes/no), endocrine therapy (yes/no), lymph node status (0, 1, 2-4, &gt;4), combined expression of IHC-measured ER (pos = any expression), PgR (pos if any expression) and HER-2 (positive = IHC2/3+ and FISH pos), architectural, nuclear and mitotic score. Univariable and multivariable proportional hazards Cox regression using the Firth's penalization method to reduce bias in the parameter estimates were used.
Results: Of the 1013 patients in the dataset, 14 had missing values (1.4%). With a median follow-up of 80 months, we observed 116 BCRE (11.6%); 43 local and 73 metastatic. In univariable analysis, screen detected cancers showed better (HR 0.63, 95% CI 0.42-0.93) and palpable cancers worse prognosis (HR 1.96, 95% CI 1.13-3.71) than non-screen detected and non-palpable cases respectively. The beneficial univariable effect of screening weakened in the multivariable analysis (HR 0.83, 95% CI 0.52-1.31) as 582/602 (97%) of non-screen detected cancers were palpable vs 227/397 (57%) for screen-detected cancers. If palpable was omitted from the multivariable model the HR of screening decreased to 0.68 (95% CI 0.44-1.03) thereby approximating its univariable result. Conclusion: Overall, palpability is more strongly related to prognosis, but detection method also has an effect even though we do not have enough events to show this with a convincing level of reliability.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-09.
Abstract P4-09-10: Prevalence of Triple Negative Breast Cancer (TNBC) and Its Management in 3 Large Breast Cancer Centres in Australia: A Retrospective Review
Authors: Chan A , Lewis C , de Boer R. 
Published: April 2011

Abstract
Background:
Triple negative (ER, PR, HER2 negative) breast cancer (TNBC) is a recognised subtype of invasive breast cancer (BC) associated with a worse prognosis. It represents 10-15% of BC and currently there is no tailored therapy in the adjuvant or metastatic setting. Review of outcomes in BC patients (pts) treated by conventional cytotoxics, can provide some understanding as to efficacy of currently used agents and provide an indication of rates of recurrence and disease response to chemotherapy in a non-trial setting. Methods:
The databases of 3 large Australian centres were examined for BC patients with TN tumours defined as: ER and PR negative on immunohistochemistry (IHC) and HER2 negative by either IHC 0 or 1+ or on ISH. Data was entered prospectively and collectively analysed for prevalence, management and outcome of pts with TNBC seen between January 1998 — December 2009. Pt and tumour characteristics were compared to those with non-TNBC. For the TNBC cohort, details on adjuvant chemotherapy given and relative dose intensity (RDI) was assessed. Disease-free survival, breast cancer event rate and systemic treatment given and response in the first-line metastatic setting will be reported. Results:
Over the 12 yr period, 4902 BC pts were seen with 643 (13%) TNBC (98% operable and 2% metastatic at diagnosis). Median age was 51 years (range, 24-90) and 40% were premenopausal at diagnosis. Tumour characteristics for the entire group are shown in Table 1 and adjuvant treatment given to pts with TNBC in Table 2.
With a median follow-up (mfu) of 36 months (m) (0.2-142), 184 BC events occurred in 154/643 pts (25%). First event was CBC 3.5%, local recurrence 6.7%, metastatic 16.4% (Lung 37%, Lymph nodes 34%, Bone 31%, Liver 27%, CNS 9%). The median DFS was 33m with 77% of BC events occurring within 5yrs. Of the 105 pts who died from BC, median time from metastatic diagnosis to death was 10 months (0.1 - 65). Conclusions:
In 3 large oncology institutions, 13% of new pts with BC had TNBC. Despite adequate dose delivery of anthracycline/taxane/combination anthracycline-taxane adjuvant chemotherapy in 78% of these pts, 25% of pts had a BC event at mfu of 3yrs. Despite the majority of pts receiving taxane, capecitabine or anthracyclines in the first-line metastatic setting, median survival was only 10 months, with 75% of pts dying by 2 yrs from metastatic diagnosis. More effective therapies are required in both the adjuvant and metastatic setting for treatment of this aggressive subtype of BC.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-10.
Abstract P4-09-14: Invasive Lobular Carcinoma Is a Prototype of Luminal A Breast Cancer Subtype and Rare in Korea
Authors: Jung S-Y , Kwon Y , Kim E-A , Ko KL , Shin KH , Lee KS , Park IH , Lee S , Kim SW , Kang H-S , Ro J. 
Published: April 2011

Abstract
Purpose Invasive lobular carcinoma (ILC) is known to be the second most frequent histologic subtype, occupying 10% of invasive breast cancer in the Western countries. The present study was designed to assess the clinical characteristics and outcomes of ILC compared to general invasive ductal carcinoma (IDC) and the luminal A subtype (LA-IDC).
Methods The study population included d 2916 patients with invasive breast cancer consecutively diagnosed at the National Cancer Center, Korea between 2001 and 2008. The clinicopathological characteristics and clinical outcomes were retrospectively reviewed.
Results There were 83 pts (2.8%) diagnosed with ILC and 1,088 pts (37.3%) with LA-IDC. Mean age was 48.2 years of all patients, 48.3 years of ILC group and 47.9 years of LA-IDC group. The ILC patients presented with a larger tumor size (≥T2, 59.8% vs. 38.8%, P=0.001), lower histologic grade (HG 1 or 2, 90.4% vs 64.4%, P&lt;0.001), more often estrogen receptor (ER) and progesterone receptor (PgR) positivity (ER+, 90.4% vs. 64.4%, P&lt;0.001; PgR+, 71.1% vs. 50.1%, P&lt;0.001), HER2 negativity (97.5% vs. 74.9%, P&lt;0.001), lower Ki-67 expression (10.3% ± 10.6% vs. 20.6% ± 19.8%, P&lt;0.001), and luminal A subtypes (91.4% vs. 51.2%, P&lt;0.001) compared to the IDC group. Six (7.2%) ILC patients and 359 (12.7%) IDC patients developed disease recurrence with a median follow-up of 56.4 months (range 4.9-136.6 months). Although ILC showed similar prognosis to IDC in general (5-year DFS rate, 91.7% in ILC vs. 87.4% in IDC, P=0.31; 5-year OS rate, 93.6% in ILC vs. 92.5% in IDC, P=0.38), its outcome was closer to LA-IDC, and better than non LA-IDC (LA-IDC (ref); ILC, HR 0.77 in recurrence, 95% CI 0.31-1.90, P=0.57; HR 0.75 in death, 95% CI 0.18-3.09, P=0.70; non LA-IDC, HR 1.69 in recurrence, 95% CI 1.23-2.33, P=0.001; HR 1.50 in death, 95% CI 0.97-2.33, P=0.07) in univariate and multivariate analysis.
Conclusions ILC is a very rare histologic subtype of breast cancer in Korea compared to the Western countries and has distinctive clinicopathological characteristics similar to those of LA-IDC. Acknowledgement: supported by NCC grant #0910320
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-14.
Abstract P4-09-18: Triple Negative Breast (TNBC) Cancer in Hispanic Population: Clinicopathological and Recurrence Features
Authors: Gómez HL , Velarde RG , Neciosup SP , Cruz WR , Mas LA , Suazo JF , Pinto JA , Vigil CE , Vallejos CS. 
Published: April 2011

Abstract
Background: TNBC is characterized by the lack of hormonal receptors and HER2 expression and occurs most frequently in Black and Hispanic than in Caucasian population. We compare clinicopathological and outcome variables between TNBC and non-TNBC Hispanic patients (pts). Methods: We reviewed 1044 cases of operable breast cancer treated at INEN, Lima-Perú (2000 — 2002). Phenotypes were categorized by IHC into TNBC and non-TNBC. Variables in both groups were compared with the X2 test. We used Kaplan-Meier method for comparing disease free survival (DFS), overall survival (OS), post recurrence survival by phenotype (TNBC v non-TNBC) and the hazard rate (HR) for different times. Results: 212 pts (20.3%) were TNBC and 832 non-TNBC (79.7%); median for age was 48 and 49 years (y), for tumor size 3.5 and 2.9cm; TNBC was more likely to have involved nodes (55.7 v 45.6%; P=0.009), tumors &gt; 5cm (14.2 v 8.1%; P=0.011) and histological grade 3 (62.7 v 29.0%; P&lt;0.001). Recurrence rates (RR) were 25.9 v 22.5% (TNBC v non-TNBC). TNBC and non-TNBC present different RR.
Recurrence sites and phenotype
Median of follow-up was 7.63 and 7.57y; there was not significant differences for DFS between TNBC and non-TNBC (72.8 v 76.6%;P=0.057), but in OS had differences (73.2 v 79.9%; P=0.014). The HR for recurrence was calculated to 1y (7.9 v 2.7%); 2y (8.8 v 5.8%); 3y (8.0 v 6.5%); 4y (2.7 v 3.3%) and to 5y (3.5 v 3.9%) and the HR for death to 1y (4.3 v 0.8%); 2y (6.7 v 2.6%); 3y (8.4 v 3.8%); 4y (5.5 v 2.8%) and to 5y (2.6 v 4.5%) for TNBC and non-TNBC, respectively. HR for recurrence and death was higher in TNBC until the first 3y and 4y, respectively, then HR were similar for both groups. Post recurrence survival show differences between TNBC and non-TNBC (HR=1.7; 95% IC 1.2 - 2.3; P=0.002). Conclusion: In early breast cancer, TNBC is more aggressive than non-TNBC; present a higher RR in brain, distant nodes and other soft tissues; strongly time-dependent HR for recurrence and death, and a worse Post recurrence survival.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-18.
Abstract P4-09-19: The Naïve-Bayes Decision Tree (NBTree) Classifier — Predicting the Probability of Survival in Breast Cancer
Authors: Al-Allak A , Leonard R , Lewis PD. 
Published: April 2011

Abstract
Introduction
As clinicians we are commonly asked by patients ‘what is my chance of surviving breast cancer?’ A number of methods have been in use in anattempt to provide an answer including the TNM classification and the Nottingham Prognostic index (NPI). With the introduction of new machine learning methods and the vast amount of data available to us the call for new models that can predict survival more accurately. As clinicians we must question the usefulness of methods that only tell us whether a patient will survive ten years or die within that time. You may prefer to make a prognosis and be able to predict the likelihood of survival or death within a chosen time span. Objectives
To develop a new predictive model based on a machine learning method known as the Naïve-Bayes Decision Tree (NBTree) classifier.
Methods
Data set: The Surveillance, Epidemiology, and End Results (SEER) data was used to build a data set of women diagnosed with breast cancer between 1990 and 1997. Inclusion criteria included: all women with a diagnosis of invasive ductal carcinoma, under the age of 70 and with a minimum follow up of ten years. Fields included in the data were tumour size, grade, number of positive lymph nodes, survival time and alive status. Model: NBTree is a classifier that combines a decision tree with a Naïve base classifier to build a model that provides the probabilities of outcome. The model was generated using the freely available statistical package R. The model was built based on tumour size, grade and number of positive lymph nodes. It was then validated using K-fold cross validation and tested on a subset of data.
Results
A total of 50,895 women were included in the analysis. The model was generated a total of 10 times and validated using 10-fold cross validation.
The model was able to correctly classify patients 69.26% of the time. When tested on a sub-group of the data set (2000 cases) the model was able to correctly classify patients in 68% of the instances. Conclusion
The NBTree probablistic - machine learning method provides a robust method of putting a value or probability to ten year survival following the diagnosis of breast cancer. Our future aim is to evaluate the method on European datasets to determine its accuracy for patient management relative to existing validated systems.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-19.