bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-07-02: Significance of RB-ZEB axis in EMT phenotype of breast cancer and inhibition of ZEB by CDK4/6 inhibitor
Authors: Arima Y , Hosonaga M , Saya H 
Published: August 2014

Abstract
The retinoblastoma protein (pRB) is a key tumor suppressor that regulates the progression of cell cycles from G1 to S phase. pRB is often inactivated due to mutation, very low level expression or hyperphosphorylation by cyclin-dependent kinases (CDKs) in many cancers. We found that knockdown of pRB induced the expression of ZEB1 (zinc finger E-box binding homeobox 1), which is one of the transcriptional repressors of the E-cadherin gene, and led to epithelial-mesenchymal transition (EMT) through the ZEB-dependent pathways in breast cancer cells. EMT is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype, and is associated with an invasive and metastatic potential in cancers. We found that siRNA-mediated depletion of ZEB in pRB-inactive cells suppressed cell invasiveness and proliferation and induced epithelial-cell marker expressions. We also found that knockdown of ZEB1 reduced the dissemination of breast cancer cells in bone marrow from primary tumors growing in mammary fat pads of nude mice. We then conducted a screen with an existing drug library for inhibitors of ZEB1 expressions and identified several hits, including CDK inhibitors. We confirmed that the CDK4/6 inhibitor, Palbociclib (PD0332991), suppressed breast cancer cell proliferation and invasiveness in vitro, and the treatment with the PD0332991 suppressed tumor growth in vivo using an orthotopic xenograft breast cancer model. In terms of cancer stemness, we found that the treatment of PD0332991 decreased the CD44+/CD24Low/- breast cancer stem cell population. We also determined that CDK4 inhibitors blocked tumorsphere formations, which are a characteristic of stem-like cancer cells. p16INK4a (p16) is an endogenous CDK4/6 inhibitor, and we found that knockdown of p16 increased the CD44+/CD24Low/- breast cancer stem cell population in estrogen receptor-negative breast cancer. CDK4/6 inhibitors appear to substitute for the p16 functions which suppress cancer stemness. Our findings indicate that the CDK4/6 inhibitor affects tumor progression, not only through cell cycle control, but also through the suppression of EMT and stem-like properties of cancer cells.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-07-02.
Abstract P1-13-04: A comparison of cardiovascular outcomes in postmenopausal women treated with aromatase inhibitors versus tamoxifen in breast cancer
Authors: Fiorino LH , Pitz M 
Published: August 2014

Abstract
OBJECTIVE: Breast cancer treatment Phase III studies show that Aromatase Inhibitors (AI) provide a longer disease free survival period compared to tamoxifen although overall survival is not consistently improved. This suggests an increase in a competing risk. The purpose of this study is to determine if there is an increase in cardiovascular morbidity and mortality in postmenopausal women treated with AI versus those treated with tamoxifen.
METHODS: Using a retrospective cohort study design all postmenopausal women with breast cancer from January 1, 2002 to December 31, 2010 were identified from the Manitoba Cancer Registry (MCR). Data from these patients was requested from the Manitoba Health administrative databases for exposure, comorbidity, and outcome variables. Specifically, Drug Program Information Network (DPIN) data from 2002 to the most recent data available to determine prescriptions filled for tamoxifen and AI as a measure of exposure to these drugs. Hospital separation abstracts, physician claims data, and DPIN were used to determine comorbidity as well as new events for cardiovascular disease. Four specific groups were identified for comparison with respect to the outcomes of interest: tamoxifen exposed, AI exposed, exposure to both and no exposure. The primary end point was cardiovascular outcomes, including incident coronary heart disease and stroke.
RESULTS: There were 4729 postmenopausal women diagnosed with Stage I – III breast cancer within previously defined years. The numbers for those treated with AI, Tamoxifen or both were 1590, 1015 and 607 respectively. Excluding women with preexisting comorbidity of coronary heart disease (CHD) and stroke, a competing risk regression model found that tamoxifen at 1 year of use had a statistically significantly lower rate of CHD endpoints compared to AI (p 0.040). There was no difference in stroke incidence between the two groups.
CONCLUSION: Tamoxifen appears to provide a protective affect against CHD. Aromatase Inhibitors may lead to an increase in cardiovascular morbidity and mortality which may explain the lack of overall survival benefits with it's use. In the future, Tamoxifen may be preferentially used in women with a significant cardiac history.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-04.
Abstract P1-13-08: Arthralgia and changes in serum levels of IGF-I, its binding protein and estrogen in breast cancer patients on endocrine agents
Authors: Lintermans A , Van Asten K , Wildiers H , Paridaens R , Leunen K , Smeets A , Amant F , Christiaens M-R , Verhaeghe J , Vermeersch P , Vanderschueren D , Neven P 
Published: August 2014

Abstract
Objective Aromatase inhibitors (AIs) frequently induce or enhance musculoskeletal problems, also known as the AI-induced musculoskeletal syndrome (AIMSS). Underlying mechanisms are unknown, likely multiple and induced by low estrogen levels. We hypothesized a role for the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis (Lintermans et al, Ann of Oncol 2011). Recently, Gallicchio et al. (J Cancer Res Clin Oncol 2013) confirmed our hypothesis. Here we report the effect of tamoxifen and AIs on AIMSS, IGF-I, its binding protein and estrogen levels from a prospective study.
Material & Methods In this prospective cohort study postmenopausal women with an early breast cancer scheduled to start adjuvant endocrine therapy with any of the third generation AIs or tamoxifen were included. After providing informed consent, a rheumatologic questionnaire was completed and serum was collected. AI-induced musculoskeletal pain was defined as an increase in joint or muscle pain relative to baseline; AIMSS presence was defined as the presence of ≥ 3 out of five features (arthralgia, myalgia, joint stiffness, tingling, carpal tunnel syndrome).
IGF-I levels were determined in batch with an inhouse radio-immunoassay; levels of IGF binding protein 3 (IGFBP-3) with a commercial EASIA from DiaSource. A sensitive liquid chromatography dual mass spectrometry was used for assessment of estradiol (E2) and estrone (E1) values, with a limit of quantification of 1.3 and 1.2 ng/l, respectively. SHBG levels were determined with the Roche Modular E170 analyzer. Re-evaluation was done after 3, 6 and 12 months of therapy.
Results 84 patients started on tamoxifen (n = 42) or an AI (n = 42; anastrozole n = 6, letrozole n = 36). In the AI group, 4 patients discontinued due to AIMSS. In the tamoxifen group, 1 patient developed a deep vein thrombolic event and discontinued tamoxifen therapy.
In all BMI categories, AI and not tamoxifen decreased E1 and E2 levels below limit of quantification from month 3 onwards. SHBG values dropped on AI while they increased on tamoxifen.
AI therapy resulted in elevated IGF-I and IGF-I/IGFBP-3 ratio levels, whereas tamoxifen users had a decrease. AI-induced musculoskeletal symptoms were characterized by a higher increase from baseline in IGF-I levels and IGF-I/IGFBP-3 ratio than AI users without any complaints. Patients experiencing AIMSS showed a significant decrease in IGFBP-3 levels (p = 0.0007) and an increase in IGF-I/IGFBP-3 ratio (p = 0.07) compared to patients without AIMSS. This divergence was most pronounced at 3 months following AI start.
Conclusion These findings provide preliminary evidence that AI-induced musculoskeletal symptoms are associated with changes in the GH/IGF-I axis.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-08.
Abstract P2-02-10: Evaluation of apparent diffusion coefficient to predict grade, micro-invasion and invasion in DCIS
Authors: Hussein HM , Chung C , Moshonov H , Freitas V , Miller N , Kulkarni SR , Scaranelo A 
Published: August 2014

Abstract
PURPOSE: To evaluate the role of apparent diffusion coefficient (ADC) values in distinguishing DCIS grades and identifying the presence of micro-invasive/invasive disease.
METHODS AND MATERIALS:
REB approved study with informed consent obtained from 70 women (age 36-84) scheduled for core-biopsy with results of 71 non-invasive/high-risk breast lesions. All patients underwent surgery and were assessed pre-operatively using diffusion weighted (DWI)-MRI. Lesion size, morphology and ADC values were recorded. The Kruskal Wallis or one-way ANOVA test and Pearson correlation coefficient were used to study the association between ADC values and the analyzed MRI lesion characteristics. Logistic regression analysis was used to evaluate the ability of ADC values to predict the presence of invasion.
RESULTS:
Of 71 cases, 45.1% were imaged on a 3T magnet and 54.9% on 1.5 T. Final pathology demonstrated invasive cancer in 26.8%, micro-invasion in 18.3% and pure DCIS in 59.2%. On 3T, mean ADC value was 1.20 ×10-3 mm2/s ± 0.48 (SD) (range, 0.47 - 1.78 ×10-3 mm2/s) for non-high grade DCIS, 1.23 × 10-3 mm2/s ± 0.40 (SD) (range, 0.26 - 1.77 ×10-3 mm2/s) for high-grade DCIS, and 1.15 × 10-3 mm2/s ± 0.45 (SD) (range, 0.26 - 1.75 ×10-3 mm2/s) for invasive/microinvasive disease. On 1.5T, mean ADC value was 1.04 × 10-3 mm2/s ± 0.41 (SD) (range, 0.15 - 1.85 ×10-3 mm2/s) for non-high grade DCIS, 1.01 × 10-3 mm2/s ± 0.37 (SD) (range, 0.06 - 1.76 ×10-3 mm2/s) for high-grade DCIS, and 1.11 × 10-3 mm2/s ± 0.30 (SD) (range, 0.64 - 1.76 ×10-3 mm2/s) for invasive/microinvasive disease. Based on logistic regression analysis, mean ADC value was not a significant predictor for invasiveness using 1.5 T [OR = 2.6 (95% CI (0.409, 17.12)), p = 0.3] or 3T [OR = 0.4 (95% CI (0.076, 2.399)), p = 0.3]
CONCLUSION: Mean ADC acquired using a 1.5T or 3T MRI was unable to predict high-grade or invasive disease in biopsy-proven DCIS lesions. Further work is exploring voxel-based approaches that may better appreciate tumor heterogeneity and identify sub-regions of tumor with these higher risk features.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-02-10.
Abstract P2-03-05: Relationship between 64Cu-DOTA-trastuzumab positron emission tomography uptake and assessment of HER2 by immunohistochemistry in women with advanced breast cancer
Authors: Mortimer JE , Colcher D , Frankel P , Raubitschek A , Carroll M , Conti P , Tong S , Poku K , Miles J , Bading J 
Published: August 2014

Abstract
Background: We have utilized 64Cu-DOTA-trastuzumab with PET imaging to assess the in vivo expression of HER2 in women with advanced breast cancer. We have demonstrated that a preadministered dose of trastuzumab 45 mg prior to injection of 64Cu-DOTA-trastuzumab resulted in a 75% decrease in the hepatic uptake of Cu-64, resulting in improved image quality.
Methods: Patients with biopsy confirmation of recurrent disease located outside the breast and axilla considered for study. Complete staging workup included CT of the chest, abdomen, and pelvis, bone scintigraphy and 18F FDG PET. At least 1 non-hepatic site of metastasis that was &gt; 2 cm separate from the biopsy site was also required. HER2 status was assessed by both IHC and FISH. Index lesions were identified on CT imaging. After the first two patients, all patients received a cold dose of 45mg of trastuzumab immediately prior to 64Cu-DOTA-trastuzumab to decrease liver uptake. 64Cu-DOTA-trastuzumab PET imaging was performed at 24 and 48 hours. Uptake on 64Cu-DOTA-trastuzumab was correlated with HER2 status by IHC and FISH.
Results: Fifteen women have undergone 64Cu-DOTA-trastuzumab PET imaging and quantitative image analysis. 10 patients were HER2+ (7 IHC 3+, 3 IHC 2+/FISH+), 3 patients were IHC 2+/FISH-, and 2 patients were IHC 1+. Tumor uptake by 64Cu-DOTA-trastuzumab PET max SUV was higher in HER2+ positive than HER2- patients (1.9-fold higher on day1, p&lt;0.02, and 1.7-fold higher on day2, p&lt;0.05). However, the lowest max SUV was in a HER2+ patient (HER2 2+/FISH+), demonstrating considerable heterogeneity.
Conclusion: 64Cu-DOTA-trastuzumab PET correlates with HER2+ status. However, due to high within and between patient variability, 64Cu-DOTA-trastuzumab PET imaging could potentially enrich for HER2+ patients that respond to HER2-targeted therapy, and could also suggest some HER2- patients that may benefit from HER2-targeted therapy. This hypothesis needs to be further explored in patients undergoing HER2-targeted therapy. This work was supported by the Department of Defense grant # BC095002.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-03-05.
Abstract P2-04-02: Overdiagnosis in mammography screening in two randomised trials in Malmö, Sweden – An age specific analysis
Authors: Jonsson H , Johansson R , Andersson I , Zackrisson S 
Published: August 2014

Abstract
OBJECTIVES: The aim of the current study was to estimate age-specific overdiagnosis due to mammography screening in the two randomized trials in Malmö, Sweden: The Malmö Mammographic Screening Trial I and II (MMST I and MMST II).
SETTING: Women living in Malmö were randomized in a 1:1 proportion to a screening group or a control group. The MMST I included 42,283 women born between 1908 and 1932 and the MMST II included 17,793 women born between 1933 and 1945. Women in the study group were invited from 1976 until 1990 when the control group was invited. The age at randomization was 45-70 years in MMST I and 43-48 years in MMST II.
METHODS: Data from the two trials were merged and overdiagnosis was estimated using age specific incidence rates excluding the first years of screening. The age specific relative breast cancer incidence rate for the screening group versus the control group was estimated and adjusted for lead time. Only the first breast cancer diagnosis was considered and results for invasive cancer and carcinoma in situ combined as well as for invasive cancer were calculated.
RESULTS: The number of breast cancer cases, including carcinoma in situ, for the period 1976-1989 was 867 and 676 for the study group and the control group, respectively. The rate ratio for overdiagnosis in age 43-78 years adjusted for lead time was 1.04 (95% CI, 0.93-1.16). No overdiagnosis from subsequent screening was found for women below the age of 60. In women aged 60-69 and 70-78 years overdiagnosis was estimated at 1.13 (0.95-1.33) and 1.15 (0.85-1.54), respectively. The corresponding results for invasive cancer only was lower and no overdiagnosis was seen except for the age group 60-69 years where the rate ratio was 1.10 (0.92-1.32). For age 43-78 the result was 0.96 (0.85-1.08).
CONCLUSIONS
For the total material overdiagnosis from subsequent screening, including carcinoma in situ, was 4%. This is somewhat lower than an earlier evaluation of MMST I where age were higher and another method was used. For women below the age of 60 no overdiagnosis was seen and indicated that the possible problem with overdiagnosis concern women 60+. However none of the results were statistically significant at the 5% level.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-04-02.
Abstract P2-05-04: Comparative expression profiling of patient samples and preclinical models of inflammatory breast cancer reveals gene signatures of epithelial plasticity and suppression of TGFb signaling
Authors: Van Laere SJ , Marsan M , Vermeulen PB , Viens P , Barsky SH , Cristofanilli M , Dirix LY , Bertucci F , Robertson FM 
Published: August 2014

Abstract
Introduction: Genome-wide expression profiling of samples from patients with and without Inflammatory Breast Cancer (IBC) has revealed novel insights into the biology of IBC. The present study was undertaken to compare these novel insights with data obtained from all available preclinical IBC models including 2 new models that we have recently developed that recapitulate the characteristics of IBC including retention of E-cadherin, formation of tumor emboli and encircling lymphoangiogenesis
Materials and Methods: Five replicates of 7 preclinical IBC models (SUM149, SUM190, FC-IBC-01, FC-IBC-02, MDA-IBC-03, KPL-4, and Mary-X) were profiled using Affymetrix HGU133plus2 GeneChips. Using a nearest shrunken centroid algorithm, each expression profile was classified according to an IBC-specific signature identified in patient samples. Available expression profiles were further queried for expression patterns related to Epithelial-to-Mesenchymal Transition (EMT), TGFβ-signaling and IBC-specific patterns of transcription factor activation.
Results: Application of our IBC-specific signature (posterior probabilities exceeded 0.50 in at least 4/5 replicates) revealed that out of 7 pre-clinical models of IBC, 3 of these robustly classified as IBC (FC-IBC-01, FC-IBC-02, and KPL-4). All preclinical IBC models were characterized by retention of E-Cadherin expression, absence of ZEB1 expression, attenuated expression of specific components of the TGFβ pathway (TGFβR2, SMAD3, SMAD7, and TGFβ1), and ambiguous activation patterns of several transcription factors involved in regulating cellular plasticity and cell fate decisions (Up in IBC: NR4A2, RARB/RXRA, PTX3, GSC2, and ZEB1; Down in IBC: SOX10, PAX5, and SMAD2). For each of the molecular alterations described above, Z-scores greater than 2 were achieved in at least 4/5 replicates.
Conclusions: The observations that we have made using IBC patient tumor samples with regards to EMT, cell plasticity and TGFβ-signaling are corroborated in pre-clinical models of IBC using current analytic approaches, despite the fact that expression patterns of the majority of preclinical models of IBC deviate from the IBC-specific expression patterns observed in patient samples. Our data suggest that despite their highly invasive nature, IBC cancer cells retain an epithelial cell phenotype characterized by E-cadherin expression and loss of ZEB1 which appears to be mediated by, amongst others, attenuated TGFβ-signaling. This study strengthens our hypothesis that cancer cells from IBC exhibit cohesive invasion, and invade as a unit, possibly explaining the presence of florid tumour emboli which is a primary characteristic observed in IBC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-04.
Abstract P2-07-01: Polymorphism A247S of XRCC4 contributes to the risk of breast cancer and impairs DNA damage repair pathway
Authors: He M , Hu X , Cao A-Y , Yu K-D , Shao Z-M , Di G-H 
Published: August 2014

Abstract
Genetic variations in a network of genes involved in DNA double strand breaks (DSB) repair pathway have been shown to increase the risk of breast cancer. XRCC4 is identified as a pivotal modulator in non-homologous end joining (NHEJ), a predominant DSB repair pathway. In this study, we evaluated the associations between single nucleotide polymorphisms (SNPs) in XRCC4 and breast cancer, and investigated the impact of XRCC4A247S variant on nuclear localization and DNA damage response functions of XRCC4.
A hospital-based case-control study, comprising 412 breast cancer patients and 458 cancer-free controls recruited from Shanghai Cancer Center, was conducted to investigate the relationship between common polymorphisms in XRCC4 and the risk of breast cancer. Our results showed that XRCC4A247S polymorphism (rs3734091), located near the putative nuclear localization signal (NLS) of XRCC4, was associated with a significantly increased risk of breast cancer in a recessive genetic model (Adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.09-4.52; P = 0.042). This homogeneous variant was more often observed in triple negative subtype (Adjusted OR = 2.07, 95% CI = 1.34 - 3.58 in the recessive model; P = 0.036). Although XRCC4A247S variant did not harm its interactions with XLF and ligase IV (the other two components of DNA ligase complex), we revealed that A247S alteration partially impaired the nuclear localization of XRCC4 in mammary cells. Remarkably, more evidences implied that XRCC4A247S variant significantly reduced the in vivo NHEJ repair efficiency compared to the wild-type XRCC4 via colony formation assay and NHEJ reporter assay, suggesting that reduced nuclear accumulation by XRCC4A247S variant impaired its functions in response to DNA damage. Importantly, XRCC4A247S alternation promoted cellular sensitivity to ionizing radiation and DNA damaging agents in chemotherapy.
Taken together, this study demonstrates that genetic variation of XRCC4A247S could impair NHEJ mediated DSB repair and provide further evidences that genetic variants involved in DNA repair pathways contribute to breast cancer susceptibility. In addition, our results also indicate that XRCC4A247S variant might be a potential predictive biomarker and therapeutic target in breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-07-01.