bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-05-06: Spatio-temporal computational modeling of the p53-Mdm2 pathway
Authors: Sturrock M , Thompson AM , Chaplain MAJ 
Published: August 2014

Abstract
Background: The p53 transcription factor is a well-established regulator of the cell cycle and key to preventing cancer. In response to a variety of cellular stresses (e.g., DNA damage or oncogene activation) p53 is activated and translocates to the nucleus where it activates transcription of target genes which can induce cell cycle arrest, senescence or apoptosis. One of the target genes for p53 is the gene for Mdm2, a negative regulator of p53 function in cells. Mdm2 represses p53 function through two main mechanisms: by promoting p53 ubiquitination and proteasomal degradation and, through direct inhibition of p53 transcriptional activity. Experimental data have revealed that in response to gamma irradiation, p53 and Mdm2 concentrations exhibit spatial and temporal oscillatory dynamics in individual MCF7 breast cancer cells. The precise function of these oscillations is still under investigation.
Method: Using in vitro laboratory data, we have developed a computational model to study the spatio-temporal evolution of the p53-Mdm2 pathway. The model comprises a system of coupled nonlinear partial differential equations, including transport terms and reaction kinetics. The transport is assumed to include both random (diffusion) and active mechanisms with proteins convected in the cytoplasm toward the nucleus, modeling transport along microtubules. Internal structures such as ribosomes and the nuclear membrane are also explicitly modeled.
Results: Using computational simulations we have found ranges of values for the model parameters such that sustained oscillatory dynamics occur, consistent with available experimental measurements. To bridge the gap between in vitro and in silico experiments realistic cell geometries using imported images of cells have informed our computational domain. The effects of microtubule-disrupting drugs, proteasome inhibitor drugs, and mutations in the DNA binding site of p53, have been modeled yielding data in agreement with published experimental laboratory studies.
Conclusions: This mathematical computational model enables us to compare the effects of clinically relevant therapeutic approaches at the single cell level. In particular, the precise temporal and spatial distributions of p53 can be determined and the cellular consequences modeled.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-05-06.
Abstract P5-07-03: Gallotannins and Gallic acid From Mango Fruit (Mangifera Indica L) Suppress Breast Cancer Tumor Growth by Targeting Phosphatidylinositol3-kinase (PI3K)-Akt-NF-kB Pathway and Associated microRNAs
Authors: Banerjee N , Kim H , Krenek K , Talcott S , Talcott SM 
Published: August 2014

Abstract
The cytotoxic and anti-inflammatory properties of polyphenolics have been demonstrated in numerous types of cancer and the objective of this research was to understand the post-transcriptional targets involved in anti-inflammatory and pro-apoptotic pathways in the breast cancer cell line BT474, treated with a polyphenolic extract (2.5–40µg/ml) rich in gallotannins and gallic acid from mango fruit in vitro and in athymic nude mice bearing BT474 cells as xenografts.
Results show that cell proliferation as well as tumor size and weight in vivo was decreased by polyphenolics 60% and 70% in vitro and vivo, respectively. NF-kB protein and mRNA expression as well as activation were decreased in a dose-dependent manner (0.6 fold).
The extract also inhibited PI3K-dependent phosphorylation of AKT and expression and this was accompanied by down-regulation of miRNA 126 of BT474 (2.25 fold) and in vivo. NFκB-dependent genes involved in apoptosis-inhibition, metastasis and angiogenesis, such as survivin, VCAM-1, and VEGF were also decreased, in vitro and in vivo.
A microRNA-array was also used to investigate whether microRNAs with target regions within affected genes were affected by the polyphenolic extract and results show that in addition to miR-126, miR-let-7a and miR-let-7b among others were significantly increased by the extract.
In summary the anti-carcinogenic and anti-inflammatory activity of mango polyphenolics in breast cancer cells were at least in part due to targeting miR-126 -Phosphatidylinositol 3-kinase (PI3K)-Akt-NF-kB which plays an important role in the proliferative/ inflammatory phenotype exhibited in this breast cancer cell line.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-03.
Abstract P5-10-07: Luminal A breast cancer: identification of novel circulating miRNA biomarkers
Authors: McDermott AM , Miller N , Ball G , Sweeney KJ , Kerin MJ 
Published: August 2014

Abstract
Introduction: Breast cancer is a prevalent disease in need of a reliable circulating biomarker with a role in combination with mammography to facilitate early diagnosis. Mi(cro)RNAs are a group of small molecules with ideal biomarker characteristics. The knowledge that miRNAs are aberrantly expressed in cancer, and can be detected in the circulation supports their potential role in minimally invasive cancer diagnostics. Intrinsic breast cancer subtypes provide well characterized phenotypes to study the biomarker potential of miRNAs. The aim of this study was to identify systemic miRNAs differentially expressed in Luminal A (ER+PR+HER2/neu−) breast cancer, and to study their utility as oncologic biomarkers in the clinical setting.
Material and Method: Whole blood samples were collected prospectively from women diagnosed with Luminal A breast cancer (n = 57) and healthy controls (n = 57). Luminal A phenotype was confirmed by immunohistochemistry and fluorescence in situ hybridization (FISH). RNA was extracted, reverse transcribed and a Taqman Low-Density Array (TLDA, microarray) conducted on a test cohort (10 Luminal A; 10 Control). Differentially expressed miRNAs were identified using Artificial Neural Networks (ANN). Expression of specific miRNAs were validated using RQ-PCR on an independent whole blood cohort (n = 47 Luminal A; n=47 Control) and tissue (n = 30). Results were analyzed using Q-Base and Minitab V16.0.
Results: The microarray performed on the test cohort identified 77 differentially expressed miRNAs. Artificial Neural Networking highlighted seven miRNAs for further analysis (Table 1).

RQ-PCR quantification of expression of these seven candidate miRNAs in the validation group confirmed the biomarker potential of two miRNAs. MiR-181a and miR-652 were significantly under-expressed in the cancer group compared to the control group (p = 0.005 and p = 0.001 respectively). Circulating miR-181a expression correlated with invasive tumour size (r = −0.592, p = 0.008). Furthermore, a combination of these two miRNAs provided a sensitivity and specificity for detection of Luminal A breast cancer of 70% and 65%, respectively (Area Under the Curve, AUC=0.77). MiR-181a and miR-652 were also under-expressed in Luminal A tumor tissue compared to Tumor Associated Normal (TAN, p = 0.019 and p = 0.001, respectively).
Conclusion: This study provides insight into the underlying molecular portrait of the Luminal A subtype by identifying 77 miRNAs with altered systemic expression levels. Two novel miRNA oncologic biomarkers are identified, which are altered in both the tumor and circulation. These miRNAs may have a role in combination with mammography to facilitate accurate subtype-specific breast tumor detection.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-07.
Abstract P5-10-11: Clinical significance of microRNA expression as a prognostic factor in early N+ breast cancer (BC)
Authors: Ciruelos EM , de Velasco GA , Castañeda C , Rodriguez-Peralto JL , Gamez A , Sepúlveda JM , Cortés-Funes H , Castellano DE , Fresno JA 
Published: August 2014

Abstract
Background: microRNAs (miRNAs) are small noncoding RNA molecules that post-transcriptionally regulate gene expression. In the present study, we describe miRNA expression in early node-positive BC and identify a 8-miRNA score that could contribute to prognosis assessment.
Methods: First, microarray analysis was performed using RNA samples extracted from primary breast cancer. The expression of miRNAs was analyzed by RT-qPCR using the TaqMan Arrays from Applied Biosystems. After a suitable normalization of the 677 miRNAs analyzed, 123 presented a good correlation between their levels of expression in frozen tissue and paraffin tissue. A supervised analysis was done in order to identify MIR that could predict relapse.
Results: 172 patients with node-positive chemotherapy-treated early BC were included in the present study. The median age at diagnosis was (53.7) years, 128 cases (74.4%) had positive estrogen receptor, and 163 patients (94,7%) received adjuvant chemotherapy. After a median follow up of 8,1 years, 71p (41.2%) relapsed. Supervised analyses identified 8 microRNAs (has miR-30e, miR-30a, miR-21, miR-210, miR-93, miR-150, miR-99b, miR-572) associated with higher risk of relapse (5 year PFS 50% vs 90%, HR 3.75, 95% CI 2.27–6.19) and with estimated overall survival (median not reached, HR 4.51, 95% CI 2.36–8.61). Interestingly, miRNAs defined 2 prognostic groups (high and low risk) regardless of type of adjuvant chemotherapy (with or without anthracyclines) and histological subtype (luminal A, B or triple negative).

Conclusions: This study suggests that miRNA expression could contribute to assess molecular prognosis of breast cancer and identifies clusters of miRNAs that could improve outcome prediction. A validation study in node-negative and triple negative disease is planned.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-11.
Abstract P5-14-02: Women's responses to changes in US Preventive Services Task Force mammography screening guidelines: results from focus groups among ethnically diverse women
Authors: Bluethmann SM , Allen JD , Hernandez C , Opdyke KM , Gates-Ferris K , Hurlbert M , Harden E 
Published: August 2014

Abstract
Introduction: In 2009, the US Preventive Services Task Force (USPSTF) changed its recommendations on the age and frequency for routine mammography. To this point, responses to this change among ethnically diverse women have been not been well examined. The objective of this qualitative study is to describe women's awareness of the change in mammography screening guidelines by the U.S. Preventive Services Task Force and to describe their attitudes toward this change.
Methods: White, Black and Hispanic women ages 40–49 years were recruited from a variety of community settings in the Greater Boston, MA area to participate in focus groups (k = 10; N=73). Groups were segmented by race/ethnicity (Black = 29%; White=29%; Hispanic=15%). Women were asked if they were aware of the change in USPSTF guidelines, and if so, their understanding about reasons for this change and intention to comply. Focus groups were audio-taped and transcribed verbatim. Thematic content analysis was used to cull recurring discussion themes.
Results: Most women in this study were not aware of changes in the USPSTF mammography screening guidelines. Those who were aware of the guideline change were highly suspicious that it was motivated by a desire for cost savings on the part of insurance companies and/or providers. Concerns regarding the accuracy of mammography, pain associated with screening, and fear of receiving positive test results were prevalent. Nevertheless, most said that they did not intend to comply with changes in guidelines; many believed that regular (yearly) mammography should start at a young age (40 or before) and continue indefinitely.
Conclusion: Most women in this sample were unaware about changes in mammography screening guidelines and lacked understanding regarding underlying reasons for the change. Communication about the rationale for changes in mammography screening guidelines has left many women unconvinced about the potential downsides of screening and has generated a high degree of mistrust of insurance companies and medical providers.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-14-02.
Abstract P5-14-03: Breast cancer screening and follow-up of abnormal mammogram results: A population-based study comparing results from an urban university cancer center to a national database.
Authors: Mitchell EP , Avery TP , Jaslow RC , Berger AC , Lee SY , Vaughan-Briggs C , Bonat J 
Published: August 2014

Abstract
Background: To improve access to screening, the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) was developed through the Centers for Disease Control and Prevention (CDC) to provide low-income, and uninsured underserved women access to timely breast and cervical cancer screening and diagnostic services. This population-based study investigates the demographics and diagnostic outcomes of women who underwent breast cancer screening through this program established at an urban university cancer center compared to data obtained from the national program database.
Methods: The Kimmel Cancer Center at Jefferson (KCC) launched its screening program with resources from the CDC, the State of Pennsylvania, and the Susan G. Komen Foundation in 2008. The core of the program is staff lead by a Social Worker/Navigator who connects patients to education and screening services, institutional information and guidance, and follow-up to minimize barriers to access, lessen dropout, and ensure follow-through for timely diagnosis and treatment. Working with our Community-Based partner organizations, uninsured and underinsured women in Philadelphia are able to seamlessly travel from education and screening through to treatment and support. All KCC patients evaluated through this program from 2008–2011 were included and records of the NBCCDP database 2006–2010 for this study and analyses.
Results: KCC has a substantially larger African American (54.44% vs. 13.8%), smaller Hispanic (8.59% vs. 27.6%), larger percentage of abnormal mammograms (25.96% vs. 14%), higher breast cancer diagnosed per mammogram (2.13 vs 1.0) and a much younger population than the national cohort. Fewer than 1% of KCC patients have been lost to follow-up.
Conclusions: The KCC Breast and Cervical Screening and Treatment Program Services reaches a highly vulnerable and at-risk population, has a higher abnormal mammogram and breast cancer detection rate, and a higher continued participation rate than the national cohort. The Social/Worker/Navigator has a distinct role in providing follow-up for abnormal findings to minimize no-shows by providing creative problem-solving, support, counseling, finding resources to minimize barriers, and contributes significantly to the ease of operation and the continued participation of patients in the program.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-14-03.
Abstract P5-17-04: Management of Antiangiogenics' Renovascular Safety in breast cancer. Subgroup and intermediate results of the MARS Study.
Authors: Launay-Vacher V , Janus N , Daniel C , Rey J-B , Ray-Coquard I , Gligorov J , Spano J-P , Thery J-C , Jouannaud C , Goldwasser F , Mir O , Morere J-F , Oudard S , Azizi M , Dorent R , Deray G , Beuzeboc P 
Published: August 2014

Abstract
Background: Hypertension (HTN) and proteinuria (Pu) are class-side-effects of anti-VEGF drugs (AVD), related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting.
Methods: The MARS study is a multicentric prospective observational study of the renovascular safety of AVD in AVD-naive patients. in 7 centres from 2009 to 2011. There was no intervention on the choice of the AVD. Data collected included: gender, age, serum creatinine (SCr), diabetes, HTN, hematuria (Hu) and dipstick Pu. This sub-group analysis presents the intermediate results for the first 184 patients with breast cancer (BC) receiving bevacizumab who completed the 1-year follow-up (f/u) (out of 337 BC patients in total).
Results: All these 184 patients received bevacizumab (mean and median durations of treatment: 7.8 and 8 months, respectively). Median age at inclusion was 60 years. Bone, visceral and cerebral metastasis frequencies were 75.0, 52.2 and 7.1%, respectively. Diabetes and HTN prevalences were 4.3% and 10.3%, respectively. Baseline renal assessment retrieved: Pu 13.0%, Hu 8.2%, mean aMDRD 98.8 ml/min/1.73m2 and 1.1% had aMDRD&lt;60. The incidence of de novo Pu during f/u was 16.3% (Table). 58.3% of patients with Pu at inclusion improved. Among patients with de novo Pu, 42.3% afterwards improved/normalized. No grade 3/4 Pu has been reported and no hematuria. 12.7% developed HTN. In addition, renal function decreased by −3.4 ml/min/1.73m2/year and 4 patients had aMDRD&lt;60 at the end of f/u. 33.2% increased their SCr: 27.7% grade 1, 4.9% grade 2, and 0.5% grade 3. All patients with grade 2–3 returned to normal or grade 1 during f/u. No thrombotic micro-angiopathy has been reported.
Conclusion: These results show that 1) No thrombotic micro-angiopathy remains rare, 2) Pu developed in 16.3% of patients, with no grade 3/4, 3) less than 13% developed HTN, and 4) renal function was only slightly impaired with transient elevations in SCr. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM et Al. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-04.
Abstract P5-18-10: Chemotherapy can enhance trastuzumab-mediated ADCC
Authors: Tagliabue E , Sfondrini L , Regondi V , Casalini P , Pupa SM , Sommariva M , Balsari A , Triulzi T 
Published: August 2014

Abstract
Trastuzumab, a recombinant humanized monoclonal antibody directed to the HER2 protein, has shown survival benefits in women with HER2-positive breast cancer, and treatment is now FDA-approved in combination with chemotherapy. However, some patients do not respond clinically to trastuzumab, pointing to the need for further definition of trastuzumab killing activity on tumor cells to optimize this therapy. Recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in HER2-positive breast cancer patients, but the mechanism(s) underlying this synergy remains unclear. Because drug-stressed cells can dynamically regulate factors that favor activity of immune effector cells, and because trastuzumab-mediated ADCC is crucially dependent on NK cell activity, we hypothesize that this synergy reflects enhanced trastuzumab-mediated ADCC on tumor cells due to improved rather than impaired participation of immune effectors resulting from drug-induced stress. To test this hypothesis, we investigated the effect of chemotherapy in HER2-positive breast carcinoma models on NK receptor ligands and correlated the changes in these molecules with the ability of trastuzumab to mediate ADCC.
Flow cytometry revealed a 4-fold upmodulated surface expression of NKG2D (MICA, MICB, ULBP1, ULBP2) and DNAM-1 (CD112 and CD155) ligands in HER2-positive breast carcinoma cell lines BT474 and MDA-MB-361 treated for 6 hr with taxotere at a 72-hr IC50 dose, consistent with results of Western blot analysis using soluble lysates obtained from chemotherapy-treated HER2-positive breast carcinoma xenografts. The enhanced expression of NKG2D and DNAM-1 ligands in breast carcinoma cells was accompanied by about a 50% increase in trastuzumab-mediated in vitro ADCC in chemotherapy-treated versus untreated cells. Antibodies blocking NKG2D and DNAM-1, but not control monoclonal antibody, abolished the chemotherapy-induced increase of in vitro trastuzumab-dependent ADCC. Increased expression of NK ligands in taxotere-treated BT474 cells was associated with cytoskeletal damage assessed by confocal microscopy; at 72 hr after chemotherapy, NK ligands returned to basal levels, pointing to the importance of duration of NK ligand enhancement for the chemotherapy-induced trastuzumab-mediated ADCC.
Together, our results indicate that chemotherapy can modulate expression levels of NK-activating ligands on human breast carcinoma cells in correlation with trastuzumab-mediated ADCC, raising the possibility of identifying optimal chemotherapy administration schedules to maximize activity of trastuzumab-mediated ADCC effectors. (Partially supported by AIRC)
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-10.
Abstract P6-04-15: The involvement of LMTK3 in endocrine resistance is mediated via multiple signaling pathways
Authors: Giamas G , Xu Y , Filipovic A , Grothey A , Coombes CR , Stebbing J 
Published: August 2014

Abstract
We have previously identified new kinases that are able to phosphorylate and/or modulate ERα activity via a high-throughput RNA interference screening. Amongst the most potent novel regulators was LMTK3, a previously uncharacterized molecule. We found that LMTK3 confers its anti-tumor effects predominantly via ERα-regulated signaling. Evolutionary analyses revealed LMTK3 was the only kinase that has adaptively evolved and subjected to Darwinian positive selection, an intriguing and suggestive result given the unique susceptibility of humans to ERα+ breast cancer compared to the great apes (especially for chimpanzees [Pan troglodytes], our closest living relatives). Furthermore, in a large cohort of human breast cancer patients (n = 613), LMTK3 protein levels and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapy. Finally, using an established orthotopic mouse model we demonstrated that inhibition of LMTK3 significantly reduces tumor volume and bioluminescence.
Now, by performing: i) mass spectrometry (MS), ii) SILAC-based quantitative proteomics and iii) genome microarray experiments of ERα+ breast cancer cell lines (Tam-sensitive and Tam-resistant) in the presence or absence of various treatments (Tam, E2, ICI), we reveal certain genes, including well-defined oncogenes and tumor-suppressors that are statistically up- or down-regulated.
Interestingly, amongst the newly identified LMTK3-regulated genes/proteins were targets belonging to already established signalling pathways implicated in cell survival, cytoskeletal rearrangement, transformation, and autophagy.
In addition, inhibition of LMTK3 re-sensitised a Tam treatment breast cancer mouse model, to Tam treatment, leading to decreased tumour growth. Moreover, in patients' plasma samples, acquired LMTK3 gene amplification (copy number variation) was associated with relapse whilst receiving tamoxifen. In aggregate, these data support a role for LMTK3 in both innate (intrinsic) and acquired (adaptive) endocrine resistance in breast cancer.
Further results and mechanistic data concerning LMTK3 actions will be presented, placing for the first time this new kinase in the maps of signal transduction.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-15.