bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estrogen Receptor beta Exerts Growth-Inhibitory Effects on Human Mammary Epithelial Cells.
Authors: Springwald A. , Lattrich C. , Ortmann O. , Treeck O. 
Published: December 2010

Abstract
In mammary epithelium estrogen receptor beta (ERbeta) is widely expressed. Its expression is reported to decline during carcinogenesis of the breast and other tissues. In this study, we examined the consequences of a loss of ERbeta expression in mammary epithelial cells. We knocked down ERbeta transcript levels in human mammary epithelial MCF-10A cells and in MCF-7 breast cancer cells by means of stable transfection with a specific shRNA plasmid. ERbeta knockdown resulted in a significant growth increase of both cell types in a ligand-independent manner. This effect was accompanied by elevated cyclin A2 expression in MCF-10A cells and by decreased expression of growth-inhibitory p21/WAF and epithelial cell marker cytokeratine 8 in both cell lines. Transfection of ERbeta shRNA did not alter the absent proliferative estrogen response of MCF-10A cells, but conferred sensitivity to selective estrogen receptor modulator tamoxifen to this cell line. In contrast, ERbeta knockdown diminished estrogen responsiveness of MCF-7 breast cancer cells and also weakened the effect of tamoxifen on this cell line. These ligand-dependent effects only observed in MCF-7 cells exhibiting a high ERalpha/beta ratio were accompanied by smaller estrogenic repression of p21/WAF expression, an impaired tamoxifen-triggered induction of this gene and by relative downregulation of ERalpha and cyclin A2 transcript levels. Our data suggest that ERbeta exerts antiproliferative effects both on MCF-10A and MCF-7 cells in a ligand- and ERalpha-independent manner by regulation of p21/WAF or cyclin A2 gene expression. Knockdown of ERbeta in both cell types was sufficient to significantly decrease transcript levels of epithelial cell marker cytokeratin 8. The results of this study support the hypothesis that ERbeta acts as a tumor suppressor in mammary epithelium.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4152.
GPR30 and HER-2 Expression in Invasive and Metastatic Breast Cancer.
Authors: Arias-Pulido H. , Joste N. , Lomo L. , Chaher N. , Lee S. , Verschraegen C. , Meisner A. , Martinez C. , Prossnitz E. , Royce M. 
Published: December 2010

Abstract
Background: GPR30 expression, a new estrogen receptor, has been previously associated with HER-2, tumor size and metastasis in invasive breast cancer (BC) but its role in paired normal (N), invasive (I), and metastatic (M), samples is unknown. We described GPR30 and HER-2 expression in a collection of paired N/I/M samples, derived from the same individual.Materials and Methods: GPR30 and HER-2 expression was assessed by immunohistochemistry (IHC) in tissue microarrays, containing paraffin-embedded cores from 100 patients diagnosed with invasive BC. N and M samples were also available from the same patient. GPR30 expression was evaluated by an H-score (Intensity (0, negative; 1+, weak; 2+, moderate; 3+, strong) x Percentage of stained epithelial cells). HER-2 expression was evaluated per standard criteria. Log rank tests and Wald tests were employed to assess the clinical impact of these molecular targets on patient outcome based on Kaplan-Meier Product estimator and Cox Proportional Hazard Regression.Results: GPR30 was expressed in 50%, 76%, and 72% of N, I and M, respectively, samples. HER-2 (3+) was found in 14% and 18% of I and M samples, respectively. GPR30 expression in I cases correlated with expression in M cases, and HER-2 expression in I but not M cases. GPR30 expression in M cases correlated with expression in HER-2 expression in M cases. HER-2 expression in I cases correlated with expression in M samples (P&lt;0.05 for all comparisons). GPR30 and HER-2 expression were not associated with grade or stage (P&gt;0.05). GPR30 expression in I or M samples was not associated with either overall survival (OS) or BC-specific survival (BCSS)(P&gt;0.5). HER-2 expression was marginally associated with OS in I (P=0.06; Hazard Ratios (HR): 1.91; 95%CI: 0.956, 3.83) but not in M (P=0.23) cases. HER-2 was significantly associated with BCSS in I cases (P=0.03; HR: 2.39; 95%CI: 1.07, 5.32) and marginally in M (P=0.08) cases.Discussion: A previous study suggested that GPR30 expression predicted the development of metastasis. We found high GPR30 expression in both the primary and metastatic sample but the difference was not significant. While GPR30 expression was not associated with OS or BCSS, HER-2 expression was marginally associated with OS and significantly associated with BCSS in invasive cases.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4158.
Capturing Changes in the Brain Microenvironment during Initial Tumor Cell Invasion.
Authors: Lorger M. , Felding-Habermann B. 
Published: December 2010

Abstract
Brain metastases occur mostly in patients with melanoma or primary tumors in the lung, breast or prostate. As therapies against primary tumors and extracranial metastases are improving and patients live longer, the incidence of brain metastases is increasing and brain lesions are seen in 20 to 40 % of patients with advanced metastatic disease. Unfortunately, no therapies are available to treat brain metastasis efficiently.Existing in vivo models of brain metastasis focus mainly on established macrometastases, while very little is known about the initial events of tumor cell brain colonization. In the present study, we used non-invasive bioluminescence imaging and detailed immunohistochemistry to capture the early events of tumor cell interaction with the cerebral microvasculature and invasion of the brain tissue. We used MDA-MB-435 metastatic cancer cells as a model because of their aggressive metastatic phenotype, and injected the cells into the internal carotid artery of immune deficient mice. Our results show that single cancer cells extravasate into the brain parenchyma 3 to 7 days after they arrest within brain capillaries and disrupt the vessel wall, bursting the microvasculature. Cancer cell arrest and extravasation occur exclusively in small vessels that are surrounded by pericytes and lack smooth-muscle cells. Early brain colonization consistently induces local activation of astrocytes, involving heterogeneous astrocyte populations. Reactive astrocytes express high levels of MMP-9 that may assist tumor cell invasion and provide first pro-angiogenic clues. Activated astrocytes consistently persist in the vicinity of growing metastases, and potentially contribute to metastatic proliferation. Occasionally, early host responses also include microglia with stellate or a reactive amoeboid morphology. Importantly, in addition to yielding actively proliferating macrometastases, tumor cell extravasation also leads to widespread single tumor cells dispersed throughout the brain tissue. The majority of these cells remains viable but stays quiescent and does not proliferate. We speculate that the diversity in early local responses of the brain microenvironment to initial cancer cell invasion contributes to the fate of extravasated tumor cells. An early involvement of diverse host cell types might provide distinct environmental clues and co-determine whether a single cell progresses to macrometastasis or remains dormant.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4162.
Analysis of Primary Breast Tumour Stromal Cells and Their Potential Role in Disease Progression.
Authors: Hartmann M. , Dwyer R. , Kerin M. 
Published: December 2010

Abstract
It has emerged in recent years that interaction between breast cancer stromal and epithelial cells supports tumour progression through promotion of epithelial cell growth, migration and invasion. Although this is thought to be mediated through both secretion of paracrine factors and cell-cell contact, the precise mechanisms are poorly understood. The aim of this study was to further characterise stromal cells derived from primary breast tumours and potentially elucidate mechanisms through which they exert their action.Following written informed consent, specimens of human breast cancer were harvested from patients undergoing surgery. Cells were isolated from tumour (n=19) and tumour-associated normal (TAN, n=9) regions of breast tissue. Breast tissue obtained from reduction mammoplasty served as normal controls. Following tissue dissociation and digestion, stromal cells were isolated by differential centrifugation. Following culture of stromal cells, RNA was extracted, reverse transcribed and relative quantitative PCR performed using primers targeting Fibroblast Activation Protein (FAP), Transforming Growth Factor β (TGFβ), Transforming Growth Factor β Receptor II (TGFβRII), Matrix Metalloproteinase 3 (MMP3), and Vascular Endothelial Growth Factor A (VEGF A).There was a trend towards increased expression of VEGF A, TGFβRII and MMP3 in tumour compared to normal stromal cells, while the level of TGFβ expression was equivalent in all samples examined. There was a significant positive correlation between expression of the proangiogenic factor VEGF A and TGFβRII (Pearson correlation coefficient r=0.317, p&lt;0.05). There was also a significant positive correlation between expression of FAP and TGFβRII (r=0.404, p&lt;0.05).Tumour stromal cells have the potential to stimulate angiogenesis through secretion of paracrine factors such as VEGF. This proangiogenic factor is a known target of the TGFb signalling pathway. The elevated level of TGFβRII observed in this study may support TGFβ mediated upregulation of VEGF and thus promote tumour angiogenesis. Further characterisation of stromal cells and their impact on epithelial cell genotype and phenotype is critical to identify targets to inhibit initiation of the metastatic cascade.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4163.
Coexpression and Synergistic Role of Multiple Atypical Chemokine Binders in Breast Cancer.
Authors: Ou Z. , Zeng X. , Li J. , Tang L. , Gu X. , Shen Z. , Shao Z. 
Published: December 2010

Abstract
Background: The expression and role of Duffy antigen receptor for chemokine (DARC), D6 and ChemoCentryx chemokine receptor (CCX-CKR) in breast cancer have already been studied independently in the past several years. However, the relationship and importance of these atypical chemokine binders (ACB) are still unclear. In this large scale clinical study, we invastigated the characteristics of multiple ACB simultaneously. Material and Methods: The protein levels of DARC, D6 and CCX-CKR were analyzed by immunohistochemistry in 517 patients with invasive breast cancer, 29 patients with noninvasive breast cancer. All of these cases come from the Cancer Hospital of Fudan University during 2001-2006, with complete clinicopathological data and follow-up data, including survival information. Results: In the invasive breast cancer patients, triple, double and single positive expression of these ACB were 135 cases (26.1%), 154 cases (29.8%) and 121 cases (23.4%), respectively. On the other hand, 107 cases (20.7%) were complete negative. The triple positive staining was significantly conversely correlated with lymph node metastasis, disease stage, relapse-free survival (RFS) as well as overall survival (OS). DARC, D6, and CCX-CKR were independent factors that influenced lymph node metastasis and their coexpression was favorable prognostic factor for RFS and OS. Discussion: Our results confirmed that DARC, D6, and CCX-CKR play a negative role in breast cancer. Furthermore, their triple or double high coexpression is more favorable for the patients, suggesting that multiple ACB may provide better protection against metastasis and relapse by synergistically regulating chemokine network in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4166.
TrkA Overexpression Enhances Growth and Metastasis of Breast Cancer Cells, and Ku86 Is Crucial for TrkA Overexpression-Induced Breast Cancer Cell Invasion.
Authors: Lagadec C. , Meignan S. , Tastet C. , Com E. , Hondermarck H. , LeBourhis X. 
Published: December 2010

Abstract
The Trk family of neurotrophin tyrosine kinase receptors is emerging as an important player in carcinogenic progression in non-neuronal tissues. Here, we show that breast tumors present high levels of TrkA and phospho-TrkA compared to normal breast tissues. To further evaluate the precise functions of TrkA overexpression in breast cancer development, we have performed a series of biological tests using breast cancer cells that stably overexpress TrkA. We show that (1) TrkA overexpression promoted cell growth, migration and invasion in vitro; (2) overexpression of TrkA per se conferred constitutive activation of its tyrosine kinase activity; (3) signal pathways including PI3K-Akt and ERK/p38 MAP kinases were activated by TrkA overexpression and were required for the maintenance of a more aggressive cellular phenotype; and (4) TrkA overexpression enhanced tumor growth, angiogenesis and metastasis of xenografted breast cancer cells in immunodeficient mice. Moreover, recovered metastatic cells from the lungs exhibited enhanced anoikis resistance that was abolished by the pharmacological inhibitor K252a, suggesting that TrkA-promoted breast tumor metastasis could be mediated at least in part by enhancing anoikis resistance. Together, these results provide the first direct evidence that TrkA overexpression enhances the tumorigenic properties of breast cancer cells and point to TrkA as a potential target in breast cancer therapy.In a second step, we used a proteomic-based approach to identify proteins involved in TrkA overexpression-stimulated invasion of MDA-MB-231 breast cancer cells. Proteins from control and TrkA overexpressing cells were separated using a cup-loading two-dimensional electrophoresis system before MALDI and LC-MS/MS mass spectrometry analysis. Among several putative modified proteins, Ku86 was found to be the major protein which was increased in TrkA overexpressing cells. Moreover, Ku86 was co-immunoprecipitated with TrkA and its level at the cell surface was increased in TrkA overexpressing cells. Interestingly, inhibition with small-interfering RNA and neutralizing antibodies showed that Ku86 was required for TrkA-stimulated cell invasion. Together, these data allowed the identification of Ku86 as a new player involved in metastasis of breast cancer cells.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4169.
FGFR1 and FGF Coamplification in Breast Cancer.
Authors: Albiges L. , Albiges L. , Quidville V. , Valent A. , Mathieu M. , Drusch F. , Job B. , Koscielny S. , Delaloge S. , Andre F. , Andre F. 
Published: December 2010

Abstract
Background:FGFR1 is a tyrosine kinase receptor involved in cell proliferation, migration and differentiation. FGFR1 gene is amplified in about 10% of breast cancer. Several studies have previously reported that FGFR1 inhibition could lead to a decrease in cell proliferation. Recent data obtained in prostate cancer have shown that FGFR1 activation could mediate epithelial to mesenchymal transition. In the present study, we evaluated the rational to target FGFR1 in clinical setting.Material and methods:We first assessed whether FGFR1 amplification was associated with a specific breast cancer phenotype. We assessed FGFR1 amplification by CGH array on 235 samples and by FISH (Z-2072, Spec FGFR1/Cen8 dual color probe, Zytovision®) on 260 samples, not included in the CGH part. We then assessed the functional effects of FGFR1 inhibitions in vitro. The antiproliferative effect of E3810 (FGFR1 inhibitor) was assessed both on FGFR1-non amplified (T47D/MCF7) and FGFR1 amplified (SUM44PE/MDA134) cell lines. Effect of FGFR1 inhibition was assessed on gene expression profiling.Results:When assessed by FISH, FGFR1 amplification was observed in 23/260 cases. Most of the samples (62%) exhibited an ER+/PR- phenotype, suggesting activation of intracellular kinase. FGFR1 amplification was observed in 24 out of 235 samples (10%). Interestingly, FGFR1 amplification was associated with gene gain in FGF3/FGF4/FGF19 (11q13) (55% versus 22%, p=0.05). FGFR1 inhibition by E-3810 inhibits MAPk phosphorylation, cell proliferation. A differential IC 50 for cell proliferation was observed between amplified cell lines and control cell lines. Preliminary data on gene expression profiling suggest that FGFR1 inhibition on breast cancer cells could lead to significant decrease in the Sox9 expression, a protein involved in epithelial to mesenchymal transition.Conclusion:FGFR1-amplified breast cancers present a discrete phenotype, including a high rate of ER+/PR- and high rate of FGF3/4/19 gains. Pharmacologic inhibition of FGFR1 leads to cell proliferation decrease and modulation of genes involved in EMT. These data suggest that there is a rational to target FGFR1 in clinical setting in patients with FGFR1-amplified breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4170.
Quantitative Analysis of HER2 Receptors Expression In Vivo by Near-Infrared Optical Imaging.
Authors: Capala J. , Chernomordik V. , Hassan M. , Zielinski R. , Gandjbakhche A. 
Published: December 2010

Abstract
Purpose: HER2 overexpression has been associated with a poor prognosis and resistance to therapy in breast cancer patients. However, up to now, quantitative estimates of this important characteristic have been limited to ex vivo ELISA essays of tissue biopsies and/or PET-based analysis. We aim at developing a novel approach in optical imaging, involving specific probes that do not interfere with the binding of the therapeutic agents, thus, excluding competition between therapy and imaging. Affibody-based molecular probes seem to be ideal for in vivo analysis of HER2 receptors using near-infrared optical imaging. To achieve quantification of HER2 receptors and overcome experimental uncertainties, we analyze post-injection temporal variations of the fluorescence intensity in the tumor area.Experimental design: Quantitative in vivo near-infrared imaging uses HER2-specific albumin-binding domain-fused-(ZHER2:342)2 Affibody molecules, labeled with AlexaFluor750 dye, as targeting agents. Subcutaneous tumor xenografts, expressing different levels of HER2 (BT474, MDA-MB361, MCF7, U251), are imaged at different times post-injection. Mathematical modeling allowed assessment of correlation between measured characteristics and HER2 expression levels from ex-vivo assays of the same tumors.Results: Affibody-Alexa Fluor conjugates may be used as a specific near-infrared probe for the non-invasive imaging of HER2-positive tumors, while analysis of the imaging parameters, directly estimated from the sequence of optical images, provides quantitative insight on the HER2 overexpression, as suggested by observed correlation between tumor cell amplification/overexpression of HER2, and these parameters.Conclusions: Method might potentially be employed in clinic for noninvasive monitoring of the HER2 expression variation in response to therapeutic intervention.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5002.
The Role of FDG PET/CT in Patients with Locoregional Breast Cancer Recurrence and a Comparison to Conventional Imaging.
Authors: Aukema T. , Rutgers E. , Vogel W. , Teertstra H. , Oldenburg H. , Vrancken Peeters M. , Wesseling J. , Russell N. , Valdés Olmos R. 
Published: December 2010

Abstract
Background: The prognosis and clinical management of patients with locoregional recurrence of breast cancer depends on the extent of the disease. Conventional work-up, consisting of bone scintigraphy, liver ultrasound, X-ray or CT of the thorax and MRI of the thoracic wall, may underestimate the local extent or miss the presence of distant metastases. The aim of this study was to evaluate the impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) on clinical management in patients with locoregional breast cancer recurrence amenable for locoregional treatment and compare the results with conventional imaging.Material and Methods: We performed a retrospective analysis of all patients referred for FDG PET/CT with locoregional breast cancer recurrence between January 2006 and August 2008. PET/CT findings were compared with results of additional imaging, pathology and follow-up. The impact of FDG PET/CT findings on clinical management of patients, was evaluated on the basis of clinical decisions obtained from patient files.Results: 56 patients were included. In 93% of the patients FDG PET/CT confirmed the locoregional recurrence. In 32 patients (57%) FDG PET/CT revealed additional tumour localisations. Distant metastases were detected in 11 patients on conventional imaging and in 23 patients on FDG PET/CT images (p&lt;0,01). In 25 patients (45%), FDG PET/CT detected additional lesions not visible on conventional imaging. FDG PET/CT had an impact on clinical management in 27 patients (48%) by detecting more extensive locoregional disease or distant metastases. In 20 patients (36%) unnecessary mutilating surgery was prevented and treatment was changed to palliative systemic treatment. The sensitivity, specificity, accuracy, positive and negative predictive values of FDG PET/CT were respectively 97%, 92%, 95%, 94% and 96%.Discussion: FDG PET/CT, in addition to conventional imaging, plays an important role in staging patients with locoregional breast cancer recurrence since its result changed the clinical management in almost half of the patients. FDG PET/CT could potentially replace conventional staging imaging in patients with a locoregional breast cancer recurrence.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5011.