bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYR61, Estrogen Receptor and FOXO3a: The Interplay in Aggressive Breast Carcinomas.
Authors: Espinoza I. , Liu H. , Busby R. , Lupu R. 
Published: December 2010

Abstract
Estrogen receptors (ERs) play key roles in breast cancer development and influence treatment outcome in breast cancer patients. More than 60% of human breast cancer tumors express ER and many of those are Estrogen (E2) dependent. ER positive tumors are considered to have a good prognosis; however some tumors escape to E2 requirements. Thus, the identification of molecules that regulate ER function may facilitate development of breast cancer treatment strategies. The pro-angiogenic factor CYR61 induces breast cancer cells to bypass the normal estrogen requirements for growth and acquire an estrogen-independent and antiestrogen resistant phenotype. However, the mechanism by which CYR61 regulates the hormonal response in breast cancer is not well understood. We over-expressed CYR61 in the ER positive cells MCF-7 (MCF-7/CYR61). Our results demonstrated that CYR61 induces constitutive transcriptional activity of the ER, which is independent of E2. Moreover, we demonstrated that CYR61 co-localizes with the ER in the nucleus and casually CYR61 transcriptional activity is regulated, at least in part by FOXO3a binding site. In search of the mechanism by which CYR61 that modulates hormonal response we discovered that CYR61 and FOXO3a interact in the presence of E2. This functional interplay among CYR61/ER/FOXO3a most likely plays a critical role in blocking hormone-response of breast cancer growth in vitro and in vivo. Furthermore, these studies demonstrate that CYR61 and FOXO3a are novel therapeutic targets to halt hormone-independent breast carcinomas.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5145.
Intermittent Hypoxia: Potential Factor of Resistance to Endocrine Therapy.
Authors: Yin W. , Liu G. , Di G. , Shen Z. , Shao Z. 
Published: December 2010

Abstract
Background: It has been reported that intermittent hypoxia, which is likely more prevalent than acute hypoxia in breast cancers, can cause persistent depression of estrogen receptor alpha (ER-α) expression in breast cell lines. However, it remains suspension whether intermittent hypoxia may be associated with resistance to endocrine therapy.Material and methods: The role of intermittent hypoxia in resistance to endocrine therapy was investigated in ER-α positive breast cell lines and animal models.Results: We observed that intermittent hypoxia promoted cancer cell proliferation in vitro and in vivo compared with normoxia. At both mRNA and protein levels, intermittent hypoxia induced down-regulation of ER-α and factor inhibiting HIF-1 (FIH) as well as up-regulation of hypoxia inducible factor-1 alpha (HIF-1α) and carbonic anhydrase IX (CA-IX). ER-α positive breast cancer cells under normoxic condition were capable of an intact response to ICI 182,780 (Tocris), whereas the inhibitory effect of ICI 182,780 (Tocris) was significantly reduced in those after intermittent hypoxia. Such effect was further validated with fulvestrant (Astrazeneca) in the animal models. To clarify whether intermittent hypoxia was associated with resistance to endocrine therapy, the expression of HIF-1α, a critical regulator of hypoxia-related pathway, was blocked by a reformed type of small interfering RNA (siRNA), stealth RNAi (Invitrogen), which can reduce the cytotoxic interferon response unlike conventional siRNA. Interestingly, knock-down of HIF-1α did result in the restoration of not only the ER-α expression but also the response to endocrine therapy, which was reproducible with administration of Bortezomib, a proteasome inhibitor of HIF-1α.Discussion: These data provide functional evidence that intermittent hypoxia may confer resistance to endocrine therapy in breast cancers through the crosstalk between HIF-1α and ER-α signaling, which holds a promise to overcome endocrine resistance.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5148.
Metabolic Syndrome in Breast Cancer: Paracrine Mediators in Mammary Adipose Tissue Mediated by Metabolic Dysfunction Influence Tumour Cell Proliferation.
Authors: Carroll P. , Carroll P. , Healy L. , Lysaght J. , Ennis D. , Dunne B. , Griffin M. , Boyle T. , Kennedy J. , Pidgeon G. , Pidgeon G. , Connolly E. , Connolly E. 
Published: December 2010

Abstract
Introduction:Obesity and it's associated metabolic syndrome are known epidemiological risk factors for breast cancer.¹ Adipose tissue is a potent endocrine organ secreting many factors that can potentially regulate tumour growth. The breast constitutes an excellent model to determine the paracrine mediators of adiposity on breast cancer. The aim of this preliminary study was thus to describe the adipocytokine milieu in the breast and determine what influence adiposity and metabolic dysfunction played in tumour progression.Methods:Adipose conditioned media (ACM) was produced by harvesting adipose tissue from sites adjacent to (peritumoural PT) and distal (D) to tumour in 20 fresh mastectomy specimens and cultured in serum free media for 72hrs. MDA-MB 231 and MCF-7 cell lines were then cultured with this ACM for 24-48hrs. Cell survival/proliferation was determined by BrDU assay. An in depth characterisation of adipocytokine production from each adipose depot was performed using multiplex bead arrays.Results:ACM from peritumoural/distal adipose tissue promoted cell proliferation in both cell lines. The greatest proliferative effect was observed in ER+ve MCF-7 cell line relative to controls (151.9±7.3% and 150.8±9.8% in peritumoural and distal ACM respectively), compared to ER-ve MDA-MB-231 cells (111.4±5.0, 112.0±2.5%).PT ACM from metabolically unhealthy/obese patients significantly increased proliferation in MCF-7 cells, compared to normal weight cancer patients (171±12.6% vs 135.3±9.3%, p=0.034). Similarly, adipocytokine expression reflected these changes with expression differences in IL-6 (6.72±0.09, 6.31±0.16 ng/ml p=0.028), HGF (7.5±1.3, 3.98±0.43 ng/ml p=0.028).Conclusion:Peritumoural adipose tissue from metabolically unhealthy and obese patients increased cell proliferation compared to normal weight patients. Metabolic dysfunction influenced expression of several adipocytokines in ACM. A thorough analysis of this milieu should lead to a greater understanding of how obesity/metabolic dysfunction regulate tumourigenesis in breast cancer.References:1: Lahmann PH et al: Body size and breast cancer risk: findings from the European Prospective Investigation into cancer and Nutrition (EPIC) International J Cancer 111: 762-771
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5150.
Stage-Specific Expressions of GLUT-1, GLUT-3 and GLUT-12 in Estrogen-Induced Breast Cancer.
Authors: Kocdor M. , Kocdor H. , Pereira J. , Vanegas J. , Russo I. , Russo J. 
Published: December 2010

Abstract
Increased glucose uptake and glycolysis are main metabolic characteristics of malignant cells. The glucose transporter-1 (GLUT-1), GLUT-3 and recently GLUT-12 have been shown in breast cancer cells in which estrogen play a critical role on its regulation and also associated with poor prognosis. However. the stage-specific GLUT regulation during the process of mammary carcinogenesis is unclear. In the present study we are aiming to study the GLUT expression pattern in an in vitro-in vivo model of estrogen induced carcinogenesis in which the human breast epithelial cell line MCF-10F is considered the normal counterpart E2 the transformed, C5 the invasive and T4 the tumorigenic stage. The gene expression of GLUTs was correlated with the ductulogenic pattern in a collagen matrix and the invasive properties using the Boyden chamber The RT-PCR data showed that the GLUT1 expression was downregulated in MCF10F after the treatment with 17β-estradiol (E2) and in the invasive cell type (C5), but not in the tumor cells (T4), which had no changes compared to MCF10F. C5 and T4 cells showed the highest rate of GLUT-3 expression. These cells were also found to be associated with loss of ductulogenesis, solid mass formation and higher invasion capacity. Whereas, GLUT-12 is downregulated in invasive and tumorigenic cells. We conclude that the estrogen-induced malignant transformation is associated with remarkably GLUT-3 expression, GLUT-1 re-expression at further stages, as well as GLUT-12 downregulation for transformed MCF-10F cells. (This work was supported by grant R21 ES015894from the NIEHS)
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5152.
Mir-128 Regulates the Self-Renewal of Breast Tumor-Initiating Cells through HTERT.
Authors: Yu F. , Zhu Y. , Gong C. , Jiao Y. , Song E. 
Published: December 2010

Abstract
Background: hTERT (human telomerase reverse transcriptase), which maintains telomere ends by addittion of the telomere repeat sequence TTAGGG, is increased in cancer cells and embryonic stem cells. However, whether hTERT has a role in regulating breast tumor-initiating cells remains unknown. Therefore, the regulation of hTERT in breast tumor initiating cells (BT-IC) would potentially facilitate our understanding of the etiology of breast cancer.Material and Methods: Enrichment for BT-ICs was performed by mammospheres from suspension cultures. The capacity of self-renewal and differentiation of BT-ICs were determined by mammosphere formation, immunohistochemical analysis of epithelial markers and FACS, respectively. TRAP assay was used to detect telomerase activity. The expression levels of hTERT in BT-ICs, with or without lentivirus-mediated mir-128 transduction, were determined by qRT-PCR and western blot. hTERT siRNA or lentivirus-shTERT were used to silence the expression of hTERT in BT-ICs. Differentially expressed mir-128 in BT-ICs was quantified by qRT-PCR and Northern Blot. The expression of BMI1 was determined by Western Blot.Results: hTERT, as well as telomerase activity, had a higher expression in BT-ICs, compared to the differentiated breast cancer cells. BMI1, the target of mir-128, is increased in BT-ICs. Conversely, the expression level of mir-128 is lower in BT-ICs, compared to the differentiated cells. Mir-128 over-expressing reduced the level of BMI1,as well as hTERT, in BT-ICs. Silencing BMI1 by lentivirus-shRNA transfection in BT-ICs leads to the decrease of hTERT protein level. Furthermore, BT-ICs, with hTERT knockdown, lost its ability to form mammospheres and proliferated poorly under differentiating conditions.Conclutions: mir-128 miRNA is reduced in mammospheric BT-ICs, resulting in up-regulation of BMI1, which further brought on the up-regulation of hTERT. And hTERT promotes self-renewal and blocks epithelial differentiation of BT-ICs. Therefore, mir-128 regulates BT-IC stem-cell like properties by BMI1 and hTERT.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5157.
Quantitative Copy Number Analysis of Onco- and Tumor Suppressor Genes in Invasive Breast Cancer by Dedicated Multiplex Ligation-Dependent Probe Amplification.
Authors: van Diest P. , Moelans C. , Monsuur H. , de Weger R. 
Published: December 2010

Abstract
Several genes have been shown to be implicated in the development, progression and response to therapy of invasive breast cancer. The phenotypic uniqueness (and thus the heterogeneity of clinical behavior) among patients' tumors may be traceable to the underlying variation in DNA copy number. In the present work, we sought to obtain a more complete view of copy numbers of breast cancer related genes by multiplex ligation-dependent probe amplification (MLPA) in 104 invasive breast cancers, and to assess phenotypic correlations.There was a significant correlation between the number of amplifications on the one hand and histological grade and mitotic index on the other. MLPA revealed the following frequent amplifications: MYC in 48%, PRDM14 in 34%, TOP2A in 32%, ADAM9 in 32%, HER2 in 28%, CCND1 in 26%, EMSY in 25%, IKBKB in 21%, AURKA in 17%, FGFR1 in 17%, ESR1 in 16%, CCNE1 in 12% and EGFR in 9%. Amplifications of EGFR, CCNE1 and HER2 were negatively associated with ER while FGFR1, ADAM9, IKBKB and TOP2A were positively associated with ER. Amplifications of ESR1, PRDM14, MYC and HER2 were associated with a higher mitotic index and PRDM14 and HER2 amplifications with higher grade. MYC amplification was more frequent in ductal tumors and high level MYC amplifications were significantly associated with larger tumor size. HER2-MYC, HER2-CCNE1 and EGFR-MYC co-amplified tumors were significantly larger than tumors with either of both amplifications. CDH1 (20%) and FGFR1 (10%) were the most frequently lost genes.In conclusion, gene copy number analysis with this “breast cancer MLPA kit” allowed to simultaneously assess copy numbers of 20 important breast cancer genes, providing an overview of the most frequent (co)amplifications as well as interesting phenotypic correlations, and thereby data on the potential importance of these genes in breast carcinogenesis and progression.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5168.
Multiplexed Tumor Marker Profiling at Single-Cell Resolution: Quantifying Breast Cancer Molecular Signatures.
Authors: Liu H. , Huebschman M. , Garner H. , Lane N. , Cheng L. , Rana D. , Lin A. , Hughes G. , Uhr J. 
Published: December 2010

Abstract
Excluding skin cancers, about 1.5 million new cases of cancer and about 450,000 cancer related deaths occur each year in the United States. The validation and molecular profiling of tumor markers are contributing to new paradigms in cancer research. In this presentation, we will discuss the information that can be obtained by using an Intelligent Single-Cell Optical Profiling Engine (I-SCOPE), consisting of hyperspectral imaging, multiplexed biomarker kits, and bioinformatics tools, to markedly expand the molecular profiling of tumor markers on individual carcinoma cells.Using biomarker antibodies conjugated to particular fluorochromes, we developed a multiplex of 10 different fluorochrome conjugates, one for each different tumor marker plus a nuclear dye. Staining and scanning using the I-SCOPE system showed that it can presently distinguish 10 different fluorochromes in a single pass, resulting in the identification of spatial location and relative intensity of each biomarker being interrogated. By using this system, we analyzed thousands of tumor cells from touch preparations of tumor tissue, circulating tumor cells (CTCs) in pleural fluid and blood, and disseminated tumor cells (DTCs) from bone marrow with 2 multiplex kits for a total of 17 different tumor markers. We have utilized clinically-accepted markers such as estrogen receptor (ER), progesterone receptor (PR), and HER2 in addition to biomarkers undergoing investigation such as B-cell lymphoma 2 (Bcl-2) and urokinase-type plasminogen receptor (uPAR). Furthermore, with the ability to simultaneously image 10 markers, each panel can also contain desired positive and negative controls such as CD45 (positive for white blood cells, negative for CTCs) and cytokeratin (positive for epithelial cells).The results of immunophenotyping of individual tumor cells with 17 different tumor markers indicated that the average expression of each tumor marker in 25 tumor cells was a reproducible representation of the tumor. However, comparison of individual CTCs' expression levels revealed remarkable heterogeneity in primary breast cancer cases.We conclude that hyperspectral microscope imaging together with individual tumor cell analysis represents a major step forward in developing a far more detailed and precise molecular signature of a patient's cancer. Further studies might demonstrate how it can facilitate treatment tailored to the individual patient's tumor, an important objective as new oncology drugs with specific molecular targets become more prevalent.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6002.
Grade 3 Status Dominates Prognosis in Breast Cancer.
Authors: Oliveros S. , Unger K. , Morishita M. , Davies C. , Gudi M. , Thomas G. , Leonard R. 
Published: December 2010

Abstract
Background: Histological grading (HG) is probably the most important clinico-pathological parameter that will provide information about tumour intrinsic characteristics and aggressiveness. HG is included in prognostic guidelines for treatment decision making such as St Gallen, Nottingham Prognostic Index and Adjuvant!Online. Grade 3 (G3) Breast cancer (BC) is associated with poor prognosis in terms of survival and recurrence. G3 BC reflects independent biological entities rather than being the end of the spectrum of cancer progression. Our aim is to establish the clinical relevance of HG as prognostic factor in a specific cohort of BC patients and define its relation with survival and recurrence endpoints.Method: This is a retrospective cohort analysis from 1489 operable Breast Cancer patients attending the Oncology Service at Singleton Hospital, Wales, UK between 1996 and 2002.HG was recorded for 1339 cases and outcome data were available on 1213 cases. Correlation of clinical variables with Overall Survival (OS), Distant Disease Free Survival (DDFS) and Disease Free Survival (DFS) was performed using Cox regression model.Results:The median follow-up for the cohort was 5.43 years (range 0.09 to 10.14 years) Patients were characterised according to age, HG, tumour size (TNM-T), nodal status, ER status and systemic treatment received (polychemotherapy/tamoxifen). Independent Cox regression models for each endpoint were developed based on univariate analyses. Multivariate analysis results are presented in Figure 1.Subgroup analysis of G3 cases showed a younger population: median age G3 59.4y vs G1/G2 62.9 y p:&lt; 0.001); 47.5% of G3 cases were ER positive against 94.5% of Grade 1/2 (p &lt; 0.001). Patients with G3 tumours died more rapidly from all causes (median time to death 2.22 vs 3.42 y, p &lt;0.001) and from BC (median time to death from BC 2.22 y vs 3.82 y in G1/G2, p &lt;0.001) than other HG. Similarly, G3 also relapsed quicker both distantly, (median time 1.64 vs 2.54 y G1/G2 (p&lt;0.04) and locally, median time to relapse 1.6 vs 2.35 y for G1/G2 (p&lt;0.036). There was also a significant association between grade and tumour size (median G1/G2 1.7cm vs G3 2.2cm(p&lt; 0.001); and nodal involvement and tumour size, median 1.5cm N-ve, 2.2 cm N+ve (p&lt; 0.001).Conclusion: Patients with G3 tumours tended to be younger, had a more advanced TNM staging at diagnosis and relapsed and died more rapidly than other histological grades. In our cohort, G3 tumours were adversely associated with OS, DDFS and DFS with a stronger association with these endpoints than node positivity. It is perhaps time to reconsider the HG as a prognostic factor as important as nodal status for the selection of adjuvant chemotherapy regimens.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6005.
Prelminary Results of a NEQAS Ring Study Evaluating the Ventana INFORM™ HER2 Dual Colour Single Slide ISH Assay.
Authors: Bartlett J. , Campbell F. , Ibrahim M. , Kay E. , Jasani B. , Morgan J. , O'Grady A. , Di Palma S. , Starczynski J. , Miller K. 
Published: December 2010

Abstract
Background: Recent innovations in HER2 testing include the development of novel chromogenic in situ hybridisation tests. Most countries use FISH or ISH based testing for HER2 gene amplification in equivocal (IHC 2+) cases. Data on the reproducibility and portability of novel and even established HER2 ISH methods is sparse. We report initial results from the multicentre evaluation of intra and inter-observer/site variation in scoring HER2 results from 30 breast cancers measured in 5 laboratories using the Ventana Dual colour ISH assay.Methods: A commercially available tissue micro-array (TMA; Stretton Scientific UK) containing 2 replicate cores from 30 breast cancers was circulated to 5 UK NEQAS reference laboratories (numbered 1-5). All laboratories performed chromogenic ISH using a 60 core TMA and reported results for all assessable cores. For all cases 20 cells were scored and a further 20 cells scored on a separate occasion to check intra-observer variation. Results were collated centrally and compared with FISH peformed in a single laboratory. Concordance between FISH and CISH is reported on a core by core and case by case analysis. Intra and inter-observer variation between laboratories is also assessed. Finally regression analysis comparing results was performed. Results from a single laboratory are presented here and full results will be available for the meeting.Results: 93% of cores were successfully analysed by the Ventana dual colour ISH assay. 87% of cores were successfully analysed by PathyVision® FISH CISH was concordant with FISH in 96.4% of cores evaluated. In one sample FISH results were 2.05 & 1.93 vs CISH of 2.03 and 2.14. In a second sample FISH results were 1.60 & 1.53 versus CISH results of 2.00 & 1.65. When mean results were calculated (2 cores per case) concordance between FISH and CISH results for this laboratories was 96.7% (1 discordant case – mean FISH – 1.99, mean CISH 2.09). 48 cores were scored twice (20 cells x 2) by a single observer. Mean intra-observer variation (for HER2 ratio) was 1.72% (Range 0.0-7.42%). No difference in scores was observed for the first vs second 20 cells. Scoring 40 cells produced no advantage. For results from a single observer for 2 cores (intra-site variation) from 42 core pairs (each core counted twice) variation was 7.5%.Conclusions: Preliminary evidence from the current study suggest that the Ventana INFORM™ HER2 dual colour single slide ISH assay can be robustly evaluated using conventional scoring approaches (20 cells per case). Concordance with FISH was excellent in the single laboratory reporting results to date. Further evidence will be reported from the other 4 participating laboratories.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6011.