bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1-01-10: Immune Suppression of Regulatory T Cells and M2 Macrophage in Breast Cancer Patients.
Authors: Imoto S , Sakemura N , Kamma H , Nakatsura T 
Published: June 2012

Abstract
Background: Recent multi-disciplinary treatments of breast cancer (BC) could decrease the mortality rate, but successful immune therapy remains uncertain. To explore new strategy of immune therapy of BC, we are investigating about host-tumor immune response in BC patients. Materials and methods: Tumor tissue specimens and peripheral blood mononuclear cells (PBMC) were obtained from early and advanced BC patients. PBMC were also collected from healthy volunteers. Regulatory T (Treg) cells were examined by counting CD4+CD25highCD127low/−cells in PBMC with flow cytometry analysis. Immunohistochemical evaluation of tumor specimens was performed with monoclonal antibodies of HLA-ABC and DR, CD56, CD68, CD83, and CD163. The number of stained cells was analyzed using a semiquantitative ordinal scale ranging from 0 to 3 (0, +/−, ++, +++). Results: HLA-ABC and DR were stained negative in 44% and 82% of 50 BC cases. When host-tumor immune response were compared between 38 early BC cases and 12 advanced BC cases, numbers of CD68-positive cells significantly increased in peripheral tumor tissues of advanced BC cases than in those of early BC cases (92% versus 53%). CD163-positive tumor cells were also detected more frequently in advanced BC cases than in early BC cases (75% versus 16%). There were no significant differences of distribution of CD4, CD8, CD56, and CD83-positive cells in early and advanced BC cases. Treg cells in PBMC significantly increased in percentage of the population in 37 BC patients than in 21 healthy volunteers (4.2% versus 2.5% of CD4-positive cells at mean value). Interestingly, Treg cells decreased in percentage of the population in 36 postoperative BC patients. Conclusions: Our results suggest that Treg cells render BC patients under immune suppression and M2 macrophage plays an important role of tumor progression. Targeted therapy against M2 macrophage may be a promising strategy of breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-10.
P1-01-12: Mesoporous Silicon Particles for the Presentation of Tumor Antigens and Adjuvant for Anti-Cancer Immunity.
Authors: Meraz IM , Melendez B , Gu J , Serda RE 
Published: June 2012

Abstract
Custom-made vaccines based on personalized tumor antigens are realistic options for secondary therapy, with the patient's excised tumor providing antigens. Overlap in the personalized repertoire of tumor antigens among patients also provides insight into targets for preventative cancer vaccines. Nanotechnology provides carriers for shielded delivery of antigens and presentation of immunostimulatory molecules. Rapid uptake of particles by phagocytic immune cells and migration to lymphatic tissue for antigen presentation provides opportunities to elicit tumor specific immune responses. Dendritic cells (DC) are the master antigen presenting cells (APC) for efficient processing and presentation of antigens. We have tested the ability of mesoporous silicon particles (pSi) to function as substrates for DC and to activate cells via engagement of surface toll-like receptors (TLR). pSi particles, surface labeled with lipopolysaccharide (LPS) or monophosphoryl lipid (MPL), were presented to bone marrow-derived DC. This resulted in rapid uptake of particles, with an enormous capacity for number of particles internalized per cell. Confocal microscopy studies supported higher uptake of LPS and MPL conjugated as compared to unlabeled pSi. pSi particle uptake into DC was also supported by electron microscopy imaging. TLR ligands induced morphological changes in GM-CSF stimulated cells consistent with maturation towards a DC phenotype. As expected, LPS conjugation to particles resulted in significant toxicity. MPL conjugated pSi showed little or no toxicity to DC and showed improved particle uptake into DC with morphological changes consistent with maturation towards a mature DC phenotype.The impact of cytokine cocktail on DC maturation and its impact on particle uptake were also examined. Flow cytometry analysis supported greater uptake of pSi by DC stimulated with GM-CSF and IL-4 compared to GM-CSF alone, with reduced uptake in the presence of TNF-alpha. Consistent with findings reported by others, addition of TNF-alpha to the cell media also resulted in higher levels of expression of costimulatory molecules by DC, compared to cells stimulated with GM-CSF alone. Thus immature DC are better able to internalize particle-based vaccines, with cytokine or TLR-driven maturation enhancing expression of costimulatory molecules for more effective antigen presentation.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-12.
P1-02-03: The Reciprocal Roles of E-Cadherin and ZEB1 Demonstrate the Mesenchymal-Epithelial Transition as a Primary Characteristic of Inflammatory Breast Cancer.
Authors: Chu K , Boley KM , Luo AZ , Ye Z , Wright MC , Freiter EM , Robertson FM 
Published: June 2012

Abstract
Background: Inflammatory breast cancer (IBC) is a rare but very aggressive form of breast cancer. IBC is characterized by nests of tightly aggregated cells, defined as tumor emboli, that exhibit characteristics of cancer stem cells (CSCs). IBC tumor emboli express E-cadherin which is required to maintain their integrity and our recent evidence demonstrates that expression of E-cadherin by tumor emboli is associated with lack of ZEB1 expression, a transcriptional repressor of E-cadherin. This is at odds with the current hypothesis that metastatic progression is associated with the process of epithelial mesenchymal transition (EMT), with loss of E-cadherin and gain of transcription factors including ZEB1, acquisition of CSC characteristics and enhanced invasive capabilities.
Materials and Methods: shRNA knockdown and over-expression methods, real time PCR arrays, western blotting, and in vitro assays to evaluate proliferation, invasion, growth in soft agar and clonogenicity and in vivo animal studies were used.
Results: Expression of E-cadherin was reduced by shRNA and ZEB1 was expressed in SUM149 IBC tumor cells. Numerous EMT-related genes were upregulated with loss of E-cadherin and gain of ZEB1, including N-cadherin and vimentin. However, there were marginal differences in the in vitro parameters of proliferation, Matrigel invasion and anchorage independent growth in soft agar between SUM149-shECad or SUM149-ZEB1 clones and their respective vector control cells. The loss of E-cadherin and gain of ZEB1 altered the morphology of SUM149 cells when cultured under low adherence conditions permissive for the enrichment of CSC, exhibiting a reversion in grape-like morphology to more well defined spheres, which was accompanied by increased clonogenicity in both SUM149-shECad and SUM149-ZEB1 cells. The loss of E-cadherin and the gain of ZEB1 significantly inhibited tumor growth of cells injected in the mammary fat pad of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice. Tumor volume at 56 days for E-cadherin vector control cells was 771.9 mm3 +/− 185.6 compared to shECadherin tumors, which was 13.6 mm3 +/− 7.2. Tumor volume of ZEB1 vector control tumors was 346.1 mm3 +/− 96 compared to volume of ZEB1 expressing tumors, which was 21.5 mm3 +/− 7.2.Conclusions: E-cadherin with lack of ZEB1 expression in IBC is consistent with a mesenchymal-epithelial transition (MET), consistent with the retention of the epithelial phenotype while maintaining a program of rapid metastasis and colonization of lymph nodes and distant organ sites. Furthermore, we demonstrate that the E-cadherin-ZEB1 axis is critical for the in vivo growth of IBC tumor cells. Although SUM149 cells are fully capable of undergoing an EMT process, which is under negative regulation by E-cadherin, the process of EMT does not drive in vivo tumor growth in IBC.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-03.
P1-02-05: Invasive Lobular Carcinoma – A Luminal Breast Cancer Histotype Enriched for Epithelial-to-Mesenchymal Transition Features.
Authors: Metzger O , Singhal SK , Michiels S , Ignatiadis M , Bertucci F , Galant C , Larsimont D , Salgado R , Veys I , Fumagalli D , Saini KS , Piccart M , Sotiriou C 
Published: June 2012

Abstract
Background: Invasive lobular carcinoma (ILC) represent the second most common breast cancer (BC) histotype, but little information is available about its molecular features. We sought to perform a comprehensive molecular classification of ILC and to investigate the molecular features that can differentiate ILC from invasive ductal carcinoma (IDC).
Methods: A consecutive series of 174 ILC tumors from three different centers with mininum 5-year follow-up was selected. Gene expression data were generated using Affymetrix U133 Plus 2.0 arrays. Data were analyzed by using frozen robust multiarray analysis (Matthew et al. 2009). ILC tumors were classified into BC molecular subtypes using the PAM50 classifier. Invasive Disease Free Survival (IDFS) was defined as the interval between the date of surgery and the date of any invasive recurrence or death. Multivariate analyses for 10-y IDFS containing classical clinico-pathologic characteristics were performed for different gene signatures, which were scaled so that 2.5 and 97.5% percentiles equal −1 and 1. A cohort of 90 IDC tumor samples, normalised with the same method, was used to compare expression data between ILC and IDC.
Results: ILCs were mainly characterized as luminal A (LA: 76%, n=133) and luminal B (LB:; 20%, n=34) followed by a minority of HER2−positive (2%, n=3), basal (1%, n=2) and normal-like (1%, n=2) based on Perou's classification. LB had inferior 10-y IDFS than LA in univariate cox regression analysis (HR = 1.99, 95% CI, 1.08−3.67, p=0.026). The EMT gene module was significantly higher expressed in ILC as compared to IDC (p &lt; 0.001). Adjusted hazard ratios (HR) for different gene modules investigated are detailed in the table below.

Conclusions: ILC is mainly composed of luminal tumors and a minority of HER2−positive tumors. Similarly to IDC, proliferation remains a statistically significant prognostic factor for ILC. ILC tumors were enriched with an EMT phenotype, which is not observed among IDC luminals. Of interest IGF signaling, which is known to be associated with poor prognosis in ER-positive BC, added prognostic value in this population which may open new therapeutics avenues for ILC.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-05.
P1-04-01: The Mechanism of Anti-Breast Cancer TICs Effect of Pyrvinium Pamoate Is through WNT/beta-Catenin Signaling.
Authors: Xu W , Debeb B , de Lacerda A , Li L , Larson R , Reuben J , Ueno N , Woodward W 
Published: June 2012

Abstract
We have previously shown that pyrvinium pamoate can decrease breast cancer TICs in vitro and shrink the tumor size in vivo. Although pyrvinium pamoate has been shown to target beta-catenin through activating CK-1alpha in a vitro model, the mechanism of its anti-breast cancer TICs effect is unknown. Herein, we use a constitutively active WNT/beta-catenin signaling construct EBETAP (ref) to determine if the anti-breast TIC effect of pyrvinium pamoate is through WNT/beta-catenin signaling. Using aldefluor expression and mammosphere formation efficiency as TIC surrogate assays, we found that TICs of SUM-159 transfected with EBETAP construct are resistant to pyrvinium pamoate treatment compared to control cells. Moreover, microarray analysis reveals a series of genes and signaling downstream of WNT-catenin were down-regulated in SUM-159 cells treated with pyrvinium pamoate. In summary, mechanism of anti-breast cancer TICs effect of pyrvinium pamoate is through WNT/beta-catenin signaling.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-01.
P1-04-04: Focal Adhesion Kinase Plays a Major Role in the Regulation of Human Ductal Carcinoma In Situ (DCIS) Stem Cell Activity.
Authors: Williams KE , Bundred NJ , Farnie G 
Published: June 2012

Abstract
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase that has been implicated in the regulation of normal mammary stem cells and cancer stem cells (CSCs) within mouse models. FAK is frequently overexpressed in human breast cancers but its role in human CSCs is not known. We aimed to investigate the role of FAK in human ductal carcinoma in situ (DCIS) stem cells (SCs).
We have used PF573228 to inhibit FAK activity in SUM225 (HER2−overexpressing) and MCF10DCIS.com (HER2−normal) DCIS cell lines. PF573228 inhibits the autophosphorylation of FAK at tyrosine 397 causing inactivation. Western blot analysis confirmed PF573228 (0.1-5 μM) caused a dose dependent inhibition of FAK activity in both cell lines.
The in vitro mammosphere colony assay was used to measure CSC activity in both DCIS cell lines and primary DCIS samples (n=5) (LREC#01/012). Mammosphere-forming efficiency (MFE) was calculated as percentage colony formation (&gt;60μm) in the presence or absence of PF573228 (0.1-5μM).
MFE was reduced in both the SUM225 cell line (p=0.02) and in the MCF10DCIS.com cell line (p=0.04) by PF573228 at a dose concentration of ≥0.1 μM (see Table 1). PF573228 (1 μM) also reduced mammosphere formation in human primary DCIS cells (n=5) by 18.1±5.75% when compared to control (p=0.03).

To measure the effect of PF573228 on DCIS SC self-renewal capacity we performed secondary generation mammosphere colony assays. Primary generation mammospheres that had been treated with PF573228 (0.1-5μM) were dissociated into a single cell suspension and reseeded out into mammosphere culture conditions with no additional PF573228. The mammosphere regeneration ratio (MRR) was calculated as the proportion of secondary mammospheres formed relative to the number of primary mammospheres.
MRR was reduced in both the SUM225 (p=0.005) and MCF10DCIS. com (p=0.001) cell lines after treatment with ≥0.5μM or ≥1.0μM PF573228 respectively (see Table 2). Preliminary data in human primary DCIS cells (n=1) also shows a reduction in MRR, from 0.56 to 0.14 with 0.5μM PF573228. These results suggest that CSC self-renewal capacity is reduced by FAK inhibition.

We conclude that FAK signalling is important in human DCIS SC activity measured by mammosphere growth and regeneration. Targeting FAK in the treatment of DCIS may reduce disease recurrence and improve patient outcome.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-04.
P1-04-08: Distribution of ALDH1 Positive Stem Cells in Benign Mammary Tissue from Women with and without Breast Cancer.
Authors: Isfoss BL , Holmqvist B , Alm P , Olsson H 
Published: June 2012

Abstract
Background and Aims. ALDH1 in female breast tissue has been linked to stem cells, but little is known about the benign cellular organisation in situ. We investigated the distibution of ALDH1 immunoreactive (ALDH1+) cells in histomorphologically benign breast tissue from 28 women with or without breast cancer.
Methods and Results. ALDH1+ cells were detected in benign tissue of women age 20 - 72, located most commonly within the luminal and intermediate ductular levels and in the stroma. ALDH1+ cell populations and Ki-67+ cell populations were present in separate ductules, both cell types rarely showing epithelial differentiation. ALDH1 + cells were non-reactive to Ki-67 and oestrogen receptor. Stromal round/oval ALDH1+ non-leukocyte cells in both age groups expressed contractile protein. There was a lower concentration of luminal and intermediate ductular ALDH1+ cells in post-menopausal women than pre-menopausal women, lower in cancer than non-cancer patients, and higher in women on exogenous hormones.
Conclusions. The study provides further evidence for the stem cell character of ALDH1+ cells, here in benign breast tissue of cancer and non-cancer women throughout non-lactating adult life, and contributes evidence of benign stromal ALDH1+ cells. The distribution of ductular ALDH1+ stem cells appears to be influenced by hormonal status.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-08.
P1-05-02: Epigenetic Regulation by Alcohol Reactivates Estrogen Receptor alpha in Estrogen Receptor alpha-Negative Cells.
Authors: Wong AW , Nunez N 
Published: June 2012

Abstract
Introduction: Alcohol consumption is an established risk factor for breast cancer development and contributes to mammary tumorigenesis through the regulation of estrogen receptor alpha (ERα) expression. Previously, we reported that alcohol consumption in the MMTV-neu ERα-negative mouse model of human breast cancer resulted in significantly increased ERα expression compared to non-alcohol consuming mice. Thus, our results indicated that alcohol consumption led to reexpression of ERα in an ERα-negative mouse model. Several lines of evidence suggest that ERα expression in ERα-negative cancer cells is inhibited through epigenetic mechanisms. In this study, we examine the role of alcohol on ERα reactivation through changes in histone modifications, DNA methylation, and recruitment of transcriptional regulation complexes on the ERα promoter, in vitro. Methods: ERα-negative MDA-MB-231 human breast cancer cells were treated with 0.1%, 0.2% and 0.5% v/v ethanol in culture media for 24 h. Chromatin immunoprecipitation (ChIP) assays were used to examine the enrichment of active and inactive markers of chromatin on the ERα promoter following alcohol treatment. DNA methylation at three ERα promoter CpG dinucleotide sites was assessed following alcohol treatment using methyl-sensitive restriction enzyme (MSRE)-qPCR. ChIP assays are used to determine the binding of the transcriptional regulation complexes, pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1, to the ERa promoter following alcohol treatment. MCF-7 human breast cancer cells served as an ERα-positive control.
Results: We report that histone modifications were affected by alcohol treatment in a dose-dependent manner. Enrichment levels of all five chromatin markers tested, which includes markers of active and inactive transcription, were significantly altered as a result of alcohol treatment (p&lt;0.05). We also found significantly decreased DNA methylation at three ERα promoter CpG sites as a result of alcohol treatment (p&lt;0.05). Experiments testing the recruitment of the transcriptional regulation complexes, pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1, are currently ongoing.
Discussion: ERα expression has been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, approximately one out of three breast cancers lack ERα expression at the time of diagnosis and many breast cancers lose ERα expression during the course of tumor progression. Thus, understanding the regulation of ERα expression in breast cancer cells is critical and results from this study will facilitate the development of novel therapeutic strategies and treatment options for hormone-resistant breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-05-02.
P1-06-16: BRCA2 Mutation Carriers Respond Poorly to Conventional Anthracylins/Taxanes-Based Neo-Adjuvant Chemotherapy.
Authors: Raphael J , Caron O , Rimareix F , Spielmann M , Al Ghuzlan A , Mathieu M-C , Delaloge S 
Published: June 2012

Abstract
Background: BRCA2 carriers typically develop luminal B-type breast cancers. Their exact sensitivity to conventional chemotherapy remains unclear. Promising drugs such as parp inhibitors are currently being developed in this indication. We attempted to evaluate pathological response rates of BRCA2 carriers in current the routine setting. Patients and methods: we screened our database of all patients seen at our genetic clinic over the past 15 years who were completely tested for BRCA1 and BRCA2 mutation and had received primary anthracyclines/taxanes-based chemotherapy (6-8 cycles) for invasive breast cancer as primary care. The pathological responses of pts who tested positive for BRCA2 were compared to those of BRCA1 and BRCA2-negative patients who had been diagnosed with luminal breast cancer (ER-positive, Her2-negative).
Results: Among 155 BRCA2-carriers and 503 wild-type patients, 24 BRCA2 pts and 58 pts with luminal B-type breast cancer have received primary standard anthracyclin/taxane-based chemotherapy. Median age was 38 for both populations. Median tumor size was 45 and 40 mm respectively among carriers and WT pts. 60% of BRCA2 and 100% of WT luminal B pts had ER-positive disease. A pathological complete response occurred in 18% of BRCA2 carriers and of 39% of luminal B Wt-pts. 65% of BRCA2 and 51% of WT-pts pts remained node-positive.
Conclusion: Deleterious germline mutations of BRCA2 are associated with a low probability of complete pathological response and a high risk of axillary invasion after conventional primary chemotherapy. Alternative treatments are highly expected.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-16.
P1-06-21: Relationship between Body Mass Index and Preoperative Treatment Response to Aromatase Inhibitor Exemestane in Postmenopausal Patients with Primary Breast Cancer.
Authors: Takada M , Saji S , Masuda N , Kuroi K , Sato N , Takei H , Yamamoto Y , Ohno S , Yamashita H , Hisamatsu K , Aogi K , Iwata H , Ueno T , Sasano H , Toi M 
Published: June 2012

Abstract
Background: Some studies have shown that high body mass index (BMI) is associated with inferior outcome after adjuvant therapy with non-steroidal aromatase inhibitor, anastrozole in breast cancer patients. We aimed to investigate predictive effect of BMI on clinical response to neoadjuvant therapy with steroidal aromatase inhibitor, exemestane in postmenopausal patients with primary breast cancer.
Patients and methods: The study group consisted of 109 patients from the JFMC 34-0601 neoadjuvant endocrine therapy trial in which postmenopausal patients with estrogen receptor (ER)-positive primary breast cancer were administered exemestane (25 mg/day) for 24 weeks before surgery. Patients were categorized into three groups according to BMI: low (BMI &lt; 22 kg/m2), intermediate (22 ≤ BMI &lt; 25 kg/m2) and high (BMI ≥ 25 kg/m2). Statistical analyses were performed to explore the predictive effect of BMI on clinical response using a multivariable logistic regression model.
Results: Higher BMI correlated with positive progesterone receptor status (p &lt; 0.01) and low Ki-67 index (p = 0.03). Objective response rates (ORR) were 21.7% in low BMI, 56.0% in intermediate BMI and 60.6% in high BMI, respectively (p = 0.01). In a multivariate analysis, only low BMI was an independent negative predictor of clinical response.
Conclusion: Low BMI was associated with a decreased ORR to neoadjuvant endocrine therapy with exemestane. Our results may suggest that the predictive effect of BMI varies according to the type of aromatase inhibitor and objective outcome.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-21.