bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5582: The inhibitory effects of Magnoliae Flos extract and its active components on receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and on expression of osteolytic factors in breast cancer cells
Authors: Jun Ah Young , Park Kwang-Kyun , Chung Won-Yoon 
Published: June 2012

Abstract
Breast cancer is the first of the top ten cancer killers among the female population of OECD member countries. Breast cancer cells have spread to bone easily. The bone is the preferred site of metastasis for breast cancer and is associated with significant morbidity and poor prognosis. The interaction between breast cancer cells and the bone microenvironment results in a ‘vicious cycle’ that increases both bone destruction and tumor burden. Breast cancer induces up-regulation of receptor activator of nuclear factor-κB ligand (RANKL) in osteoblast by several osteolytic factors derived from breast cancer cells, and subsequently osteoclast formation through the interaction between RANKL in osteoblasts and RANK in osteoclast precursors. Growth factors, such as transforming growth factor-β and insulin-like growth factor-1, are released from bone matrix by osteoclast-derived bone erosion. Natural plant-derived components have received much attention as sources of potential therapeutic and preventive drugs for human diseases. Magnoliae Flos (MF), the buds of Magnolia denudata Desr., is a commonly used Asian medicinal herb for symptomatic relief of allergic rhinitis, sinusitis and headache. To evaluate the inhibitory effects of MF extract and its active components (aschatin, fargesin, lirioresinol B dimethyl ether and magnolin) on cancer-associated bone disease, we first examined their effects on RANKL-induced osteoclastogenesis and bone resorption. MF extract and active components inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages in a dose dependant manner without any evidence of cytotoxicity, and bone-resorbing activity of osteoclast. In addition, MF extract and active components suppressed the mRNA expression of osteolytic factors in MDA-MB-231 human breast cancer cells, but did not affect the viability of MDA-MB-231 cells. These results demonstrate that MF extract and its active components has the potential to serve as beneficial supplements to treat and prevent cancer-induced bone diseases in patients with metastatic breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5582. doi:10.1158/1538-7445.AM2011-5582
Abstract 5585: Generation of novel cell lines for analyzing the role of TLR4 in breast cancer
Authors: Korte Mike , Rajput Sandeep , Ran Sophia 
Published: June 2012

Abstract
Background: Toll like receptor 4 (TLR4) is a transmembrane receptor expressed in macrophages that plays a major role in pathogen recognition and activation of innate immunity. TLR4 signaling has been linked to tumorigenesis and promotion of metastasis in ovarian, lung, prostate and head-neck cancers through up-regulation of the expression of inflammatory cytokines (e.g., IL-6, IL-8 and TNF-alpha). These factors increase cancer cell survival and resistance to chemotherapy through up-regulation of anti-apoptotic and down-regulation of apoptotic proteins, respectively. The goal of this study was to generate new isogenic cell lines that would allow analysis of the TLR4 role in paclitaxel resistance in breast cancer. To this end, we used TLR4-positive and negative lines (MDA-MB-231 and HCC1806, respectively) to generate stable TLR4 knockdown and over-expressing line derivatives.
Methods: To generate a TLR4 knockdown line, MDA-MB-231 cells were transfected with pisiRNA-TLR4 plasmid and selected with zeocin (50μg/ml). To generate a TLR4 over-expressing line, HCC1806 cells were transfected with pKT2-TLR4-PURO plasmid and selected with puromycin (1μg/ml). Ten to 20 monoclonal colonies were selected from each line and characterized for TLR4 expression and TLR4-dependent cell activities by qRT-PCR and western blot.
Results: TLR4 mRNA expression was reduced by &gt;90% as compared with parental line in five out of 8 MDA-MB-231TLR4− clones examined. One clone had 60% reduction and two clones had no effect on TLR4 mRNA determined by qRT-PCR. TLR4 mRNA was up-regulated 1,000-12,000 fold in five (out of 11) clones derived from HCC1806 line. Two clones overexpressed TLR4 mRNA by 300-500 fold and four clones had increased TLR4 expression by 1-6 fold. All selected clones were analyzed for TLR4 functional signaling by exposure to LPS (1μg/ml), which was reduced by 50-70% in MDA-MB-231TLR4− clones and increased by 15-25 folds in HCC1806TLR4+ sub-lines, as compared with cells transfected with empty vectors.
Conclusions: These data show that we successfully created sub-lines of MDA-MB-231 with stable knockdown of TLR4 and sub-lines of breast carcinoma HCC1806 line with stable over-expression of TLR4. Ectopically expressed human TLR4 as well as TLR4 downregulating sequence had significant functional effects on the TLR4 signaling as demonstrated by increase and decrease of LPS-activated targets (IL-6, IL-8 and TNF-alpha) in MDA-MB-231TLR4− and HCC1806TLR4+ sub-lines, respectively. These new sub-lines will serve as excellent tools for analyzing the role of the TLR4 pathway signaling in breast cancer progression, metastasis and resistance to therapy.
* These authors contributed equally in this work.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5585. doi:10.1158/1538-7445.AM2011-5585
Abstract 5591: A homologous recombination assay for classifying BRCA2 missense variants
Authors: Guidugli Lucia , Goldgar David , (Shane) Pankratz Vernon S. , Erding Catherine A. , Couch Fergus J. 
Published: June 2012

Abstract
Germline mutations in BRCA2 predispose to breast, ovarian and other cancers. Although most mutations in the gene are known to be pathogenic, there is an increasing number of missense variants for which the contribution to cancer risk is unclear. These missense substitutions are referred to as VUS (variants of uncertain significance). Because loss of BRCA2 HR function leads to defective DNA double-strand break repair and an increased risk of cancer, we evaluated the utility of a cell-based Homologous Recombination (HR) assay for determination of the cancer relevance of BRCA2 VUS.
Specifically, we studied VUS localized in the BRCA2 DNA binding domain (DBD) for effects on HR. We transfected full length wild-type and mutant BRCA2 constructs into V-C8 BRCA2 deficient cells along with an I-Sce1-expressing plasmid which induces an unique double strand break in an integrated DR-GFP reporter plasmid. We evaluated the ability of each BRCA2 mutant to repair the induced break by quantifying the GFP positive cells, generated by HR repair of the DNA break, with fluorescent activated cell sorting (FACS).
To establish the sensitivity and specificity of the HR assay we evaluated a series of known deleterious and known neutral with the HR assay. These mutations of known effect were identified using a multifactorial likelihood approach, based on available family data, with a prior probability approach based on sequence conservation (A-GVGD) algorithm (http://agvgd.iarc.fr/agvgd_input.php). We calculated the total odds of pathogenicity for co-segregation of variants with the disease in affected carrier families, co-occurrence of VUS (in trans) with deleterious mutations and for family history of cancer of VUS and combined this odds with the A-GVGD based prior probabilities to generate the posterior probability of pathogenicity for each variant. Using this approach we successfully classified 31 VUS as either neutral or deleterious. By comparing these data with results from the HR assay we established that the assay is 100% sensitive (95% CI: 75.3% – 100%) and 100% specific (95% CI: 82.4% – 100%) for deleterious mutations in the BRCA2 DBD domain.
In summary we evaluated the sensitivity and specificity of the HR assay for VUS in the DBD relative to a probability model based on family data and A-GVGD algorithm and we showed that the assay was highly sensitive and specific. Based on these results we propose that the HR assay can be used as a classifier of the clinical relevance of the VUS in the absence of direct genetic and family data.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5591. doi:10.1158/1538-7445.AM2011-5591
Abstract 560: The use of molecular biomarkers to quantify drug distribution in solid tumors
Authors: Saggar Jasdeep K. , Tannock Ian F. 
Published: June 2012

Abstract
The tumor microenvironment plays a critical role in the efficacy of chemotherapy. The disorganized vasculature within solid tumors leads to decreased drug delivery to the tumor and poor penetration of drugs from blood vessels to the tumor cells. Our laboratory has shown limited distribution of the auto-fluorescent drugs doxorubicin and mitoxantrone using quantitative immunohistochemistry. However, most anti-cancer drugs are not fluorescent and do not have antibodies that recognize them. The aim of the present study is to characterize the spatial distribution within solid tumors of biomarkers of drug effect: cleaved caspase 3 (a marker of apoptosis), γH2aX (a marker of DNA damage) and Ki67 (a marker of cell proliferation) in relation to blood vessels (recognized by an antibody to CD31). We have quantified the time-dependent distribution of these biomarkers in two models: human breast cancer MDA-MB-231 xenografts and murine mammary EMT6 syngeneic tumors following treatment with doxorubicin and melphalan respectively. Biomarker distributions have been compared to distributions of doxorubicin fluorescence. Melphalan's distribution within a solid tumor has been assessed for the first time with the use of a melphalan-DNA adduct recognizing monoclonal antibody. These studies are designed to provide a basis for selecting biomarkers to reflect the distribution of other non-fluorescent agents. The distribution of doxorubicin decreases exponentially with increasing distance from blood vessels, and is similar to the distribution of γH2aX at 10 minutes after drug injection. The activation of cleaved caspase 3 (indicating apoptosis) at 24 and 48 hours following treatment also mirrors the distribution of doxorubicin. The analysis of biomarker distributions in EMT6 tumors following treatment with melphalan in relation to tumor blood vessels is in progress. The results of these studies will be applied to quantify the intratumoral distribution of other non-fluorescent anticancer drugs (hypoxia-activated pro-drugs).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 560. doi:10.1158/1538-7445.AM2011-560
Abstract 5600: Genetic variants associated with reproductive aging and the risk of breast cancer
Authors: He Chunyan , Chasman Daniel , Ruiter Rikje , Dreyfus Jill , Porcu Eleonora , Hwang Shih-Jen , Hankinson Susan , Buring Julie , Stolk Lisette , Franceschini Nora , Sannna Serena , Lunetta Kathryn , Ridker Paul , Stricker B , Demerath Ellen , Crisponi Laura , Murabito Joanne , Hunter David 
Published: June 2012

Abstract
Early menarche and later menopause are well-established risk factors for breast cancer. Recent genome-wide association studies have identified several novel loci for these two traits. However, the association between these loci and breast cancer risk remains unknown. In this study, we investigated 19 and 17 newly identified SNPs from ReproGen Consortium that were associated with age at menarche and age at natural menopause, respectively, and assessed their association with breast cancer in 6 population-based studies. We further used these SNPs to calculate genetic risk scores (GRSs) based on their association with each trait. After adjustment for age and potential population stratification, two age-at -menarche associated SNPs (rs1079866 and rs7821178) and one age-at-natural-menopause associated SNP (rs2517388) were associated with an increased risk of breast cancer (p values, 0.003, 0.009 and 0.023, respectively); although overall we did not observe significant association between the GRSs and breast cancer risk, the 4th and 5th highest quintile of the menarche GRS had relative ratios of 1.14 (CI, 1.01 to 1.28) and 1.13 (CI, 1.00 to 1.27), respectively, compared to the lowest quintile; and these associations did not appear to be attenuated by controlling for age at menarche, age at natural menopause, or other conventional risk factors. Our study suggested that three genetic variants, independent of their association with onset of menarche or natural menopause, were associated with breast cancer risk, and a GRS that combines multiple menarche-associated SNPs might be useful for identifying a high risk subgroup for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5600. doi:10.1158/1538-7445.AM2011-5600
Abstract 5601: The role of UDP-Glucuronosyltransferases in human breast cancers
Authors: Starlard-Davenport Athena , Lyn-Cook Beverly , Word Beverly , Pogribny Igor 
Published: June 2012

Abstract
Reports of an unanticipated increase in cancer risk following exposure to tamoxifen and estrogen-containing drugs suggest that long-term consequences of genetic variations in drug metabolism may need to be elucidated more thoroughly during product development. Variations in UGTs that metabolize these drugs may result in reduced drug efficacy in estrogen target tissues, such as the breast in women. In this study, we characterized the expression of UGTs in normal (n = 31) and malignant (n = 17) human breast tissues from African American and Caucasian women. Several UGT isoforms, including UGT1A1, -1A4, -1A10, and -2B7 mRNA were down-regulated in malignant human breast specimens compared to normal breast specimens as determined by real-time PCR. In addition, UGT1A4, which is the major UGT responsible for conjugating tamoxifen, was genotyped for the UGT1A424Pro/48Val and UGT1A424Thr/48Leu variant. However, the UGT1A448Val variant was not significant prevalent within these population of samples. It is anticipated that this study will provide novel information on the role of UGTs in the breast and provide insight as to how alterations in UGT expression will impact the clearance of estrogens and tamoxifen in women. It is anticipated that this study will be instrumental in predicting tamoxifen toxicity and estrogen carcinogenicity in women with a non-functional UGT variant.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5601. doi:10.1158/1538-7445.AM2011-5601
Abstract 5602: Identification of ethnic specific differences in breast cancer and normal breast tissue
Authors: Baumbach Lisa L. , Gomez Carmen , Yan Jim , Halsey Tom , Ahearn Mary Ellen , Jorda Merce , Pegram Mark 
Published: June 2012

Abstract
Disparities in breast cancer stage of presentation and survival rates exist in patients of different ethnicities. These differences are undoubtedly a result of a combination of factors, including socio-economic, lifestyle, tumor characteristics and inherent factors, such as genetic composition. Our group is analyzing the genetic contributions to these disparities, with the goal to increase understanding of the underlying biology, leading ultimately to individualized, ethnic-specific diagnostic and therapeutic approaches. Here we report our results of a recently completed study focusing on gene expression profiling in a multi-ethnic cohort of triple negative breast cancer patients. We analyzed breast cancer and self-matched normal tissue samples from 10 African-American (AA), 10 Hispanic (His), and 10 non-Hispanic white (Caucasian) patients from south Florida. Study samples were cut from FFPE (Formalin Fixed Paraffin-embedded tissue) blocks marked by pathology as normal vs. tumor tissue, and sent to Almac Diagnostics for RNA isolation, cDNA preparation, and hybridization of tumor/normal cDNAs to a breast cancer focused gene expression array (Breast Cancer DSA Research Tool). From the Breast Cancer DSA arrays data, a two-way ANOVA (disease state and ethnicity) was used to identify transcripts with a p-value less than 0.01. Data QC indicated that samples clustered well with respect to ethnicity and adjacent normal vs. tumor tissue. We have identified ethnic-specific expression patterns in the matched normal and tumor samples. Initial pathway analysis using MetaCore Program shows that a number of genes related to the DNA repair pathway are differentially expressed across the ethnicities. In a set of ten DNA repair/cell cycle genes, the direction of change (increased or decreased expression) was the same for all three ethnic groups, however, the level of change differed greatly between ethnic groups. Fold change in this set of ten genes ranged from -6.54 to +5.53 with all being greater than 2 fold change in at least one ethnic group. Additional pathway analysis and validation of these results is ongoing. In follow up to this study, we have initiated parallel analysis in normal tissue samples (reduction mammoplasty) samples from AA and Cau non-cancer patients. Combined analysis of tumor and normal expression data will help to better understand the possible significance of gene expression differences in breast tissue between ethnic groups. These studies have important implications for addressing BC health disparities, as well as tailored approaches to prediction, prevention and treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5602. doi:10.1158/1538-7445.AM2011-5602
Abstract 5612: Identification of shared regions of genetic susceptibility to breast cancer in Arab and Jewish women with a family history of consanguinity
Authors: Gornick Michele C. , Shakour Sana , Li Jun , Rennert Gad , Gruber Stephen B. 
Published: June 2012

Abstract
Background: Breast cancer is the most commonly diagnosed cancer in Israel, and a leading cause of death among women regardless of their ethnic origin. However, younger ages at diagnosis, larger primary tumor size, and lower 5-year survival rate have been reported among Arab women compared with the Jewish women. Arabs have a high rate of parental consanguinity, ranging from 25% to 60% in different countries in the Middle East. Consanguinity leads to a higher probability of sharing alleles identical-by-descent and increased risks for autosomal recessive disorders.
Methods: Genome-wide analysis of germline DNA from 32 breast cancer patients and 26 first degree relatives was performed using the Affymetrix Human SNP Array 6.0 or the Illumina CytoSNP12 genotyping platform. Probands were screened for mutations in BRCA1 and BRCA2 to exclude common forms of inherited susceptibility. Genotype data were analyzed using PLINK to screen for runs of homozygosity of at least 500 kilobases.
Results: Long runs of homozygosity were observed in five samples, including two consanguineous Arab and 3 Ashkenazi Jewish probands. The largest region of homozygosity was on chromosome 10q23.1-25.3 which harbors several important candidate genes, including the tumor suppressor gene PTEN.
Conclusion: Preliminary analysis of breast cancer patients from consanguineous families of Arab or Jewish descent provide suggestive evidence of recessive susceptibility to breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5612. doi:10.1158/1538-7445.AM2011-5612
Abstract 5616: Assessment of differential DNA methylation by genotype in ovarian cancer cases and controls
Authors: Cicek Mine S. , Armasu Sebastian M. , Kalli Kimberly R. , Fridley Brooke L. , Sellers Thomas A. , Tsai Ya-Yu , Cunningham Julie M. , Goode Ellen L. 
Published: June 2012

Abstract
Ovarian carcinoma is a significant cause of cancer mortality in women in the United States. Increasing evidence has demonstrated that differential methylation status in lymphocyte DNA may be linked to risk of carcinogenesis. We are investigating the differential DNA methylation in germline DNA obtained from pre-treatment ovarian cancer cases (n=256) and individually-age matched controls (n=274) using the Illumina Infinium Human Methylation 27K BeadChip. We are first studying methylation and the common moderate-risk alleles for ovarian cancer on chromosomes 2q31, 3q25, 8q24, 9p22, 17q21, and 19p13. Within each locus, we correlated single nucleotide polymorphism (SNP) genotypes with methylation values at relevant nearby CpG sites. Preliminary results are available on the first set of 84 cases and 90 controls. At 2q31, cases with TG or TT genotype at rs2072590 were hypomethylated at HOXD1 (a homeobox transcription factor) compared to cases with GG genotype (mean beta TG/TT=0.08, GG=0.09, p=0.034); and at 17q21, cases with AG or GG genotype at rs9303542 were hypomethylated at SKAP1 (a T-cell adaptor protein) compared to cases with AA genotype (mean beta AG/GG=0.14, AA=0.16, p=0.045). At these two loci, similar trends were seen among controls. Logistic regression adjusted for age and methylation chip was then used to assess the association between SNP genotype and ovarian cancer risk, with and without inclusion of the relevant methylation value. At HOXD1 rs2072590, the per-allele ovarian cancer risk of 1.34 attenuated to 1.25 with inclusion of the HOXD1 methylation value as a covariate, suggesting that the disease association may be mediated in part through methylation. Though based on preliminary data, results are consistent with a role for inherited variation on germline methylation at HOXD1 and SKAP1. Analysis of methylation on additional genotyped cases and controls is underway. Finally, because, trans effects may also exist, we are assessing relationships between genotype and methylation at other loci throughout the genome. Such correlative molecular studies have the potential to help elucidate mechanisms underlying associations from genome-wide association studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5616. doi:10.1158/1538-7445.AM2011-5616