bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2-02-08: Int6 Regulates Both Proteasomal Degradation and Translation Initiation and Is Critical for Proper Formation of Acini by Human Mammary Epithelium.
Authors: Suo J , Snider SJ , Lloyd RE , Chang EC 
Published: June 2012

Abstract
The mammalian INT6/EIF3E gene has been implicated in breast tumor formation, but its functional activities remain poorly defined. Consistent with the fact that Int6 is frequently down-regulated in human breast tumors, we found that repressing INT6 expression induced transformed properties in normal human mammary epithelial cells (MCF10A) in both 2D and 3D cultures. Int6 contains a PCI domain, found in several components of both the proteasome and the translation initiation factor eIF3, suggesting that it can functionally interact with both. Indeed, our data show that Int6 associates with proteasomes in human cells, and that INT6 knockdown prevents proper assembly of active proteasomes. In addition, we show that down-regulation of INT6 reduces translation initiation (both polysome formation and global protein synthesis). However, Int6 regulates translation selectively, reducing translation from cap-dependent and Bcl2- IRES reporters, but stimulating translation from the CVB3 IRES. These data collectively suggest that Int6 controls both protein synthesis and protein degradation, and is thus capable of fine-tuning protein levels. Abnormal levels of regulatory proteins caused by Int6 abnormalities may thus be responsible for disrupting normal morphogenesis of mammary epithelial cells and causing transformed phenotypes.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-02-08.
P2-05-05: Receptor-Like Protein Tyrosine Phosphatase Kappa (PTPRK) and Its Biological Role in Angiogenesis.
Authors: Sun P-H , Ye L , Mason MD , Jiang WG 
Published: June 2012

Abstract
Introduction: Protein Tyrosine Phosphatases (PTPs) are known as signalling molecules which affect cell growth, differentiation and oncogenic transformation. PTPs have been indicated in tumourigenesis and progression of various solid tumours. PTPRK, receptor-type protein tyrosine phosphatase kappa, has been shown to down-regulate transcriptional activity of beta-catenin and impact distribution of beta-catenin/E-cadherin complexes on cancer cell membrane. However, the role played by PTPRK in angiogenesis remains unknown. In present study, the effect of PTPRK knock-down on functions and tubule formation ability of HECV cells was investigated. (or In the present study, the effect of PTPRK on angiogenesis process was investigated.)
Methods: anti-PTPRK ribozyme transgenes were constructed to knock-down PTPRK expression in vascular endothelial cells, HECV cells. The subsequent effect upon in vitro cell growth, adhesion, migration and microvascular tubule formation was examined using a variety of functional assays.
Result: Knock-down PTPRK in HECV cells (HECVΔPTPRK) resulted in a decrease of cell growth in vitro. The growth rate of HECVΔPTPRK was 276.3±16.4, p=0.01 compared with HECVpEF (314.8±21.9) controls. However, knock-down of PTPRK in HECV cells increased cell motility. The cell migration distance of HECVΔPTPRK was 83.8±19.8μm, p=0.008 compared with HECVpEF (61.8±11.8μm) controls. No effect on cell adhesion by PTPRK knockdown was seen in HECVΔPTPRK (81.2±6.6), compared with HECVpEF control (78.8±15.6). Furthermore, knock-down of PTPRK suppressed tubule formation in HECV cells, the length of total tubules (μm) in HECVΔPTPRK was 2167.4±943.2, p&lt;0.05 compared with HECVpEF (3130.6±386.9) control.
Conclusion: Knock-down of PTPRK reduced the growth and tubule formation abilities of vascular endothelial cells. It suggests that PTPRK is pivotal regulator for angiogenic process. Further investigations are required to identify the downstream pathways involved in these impacts.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-05.
P2-05-06: Role of Repulsive Guidance Molecule b (RGMb) in HGF Mediated Angiogenesis.
Authors: Sanders AJ , Ye L , Mason MD , Jiang WG 
Published: June 2012

Abstract
Introduction: Hepatocyte Growth Factor (HGF) has been widely documented as playing a key role in enhancing the aggressive nature of cancer through its ability to promote cellular processes such as migration, invasion and angiogenesis. Development of a blood supply is vital to advanced tumour growth and increased metastatic potential. In the current study we identified RGMb (DRAGON), a member of the Repulsive Guidance Molecule family, as being upregulated by HGF and assessed its potential to contribute to HGF mediated proangiogenic traits.
Methods: Expression of RGMb was identified as being upregulated in human endothelial HECV cells following 4 hour treatment with HGF (40ng/ml) using micro array analysis and Q-PCR. Subsequently, the expression of RGMb was targeted through the transfection of HECV cells with a plasmid containing a ribozyme transgene specifically targeted to RGMb. The role of RGMb in HGF mediated cellular migration and tubule formation in vitro was examined.
Results: Significant increases in RGMb expression in HECV cells were observed on the mirco-array following 4 hour treatment with HGF (P = 0.004) and this trend was also identified using Q-PCR. Transfection with the ribozyme transgene brought about substantial reductions in RGMb expression at both transcript and protein levels as assessed using RT-PCR, QPCR and Western blot analysis. Knockout of RGMb brought about a significant increase in migration rates, compared to HECV cells transfected with a closed pEF6 plasmid only (HECVpEF6), following a 90minute period (p = 0.034 at 90 minute time point vs pEF6 control). Treatment of HGF enhanced migration rates of HECV control cells with significant differences between untreated and HGF treated pEF6 cells obvious following 60 minutes (p &lt; 0.05 at 60 and 75 minutes, p = 0.002 at 90 minutes). In contrast to this, HECV cells transfected with the RGMb ribozyme transgene (HECVRGMbKO) were unaffected by HGF treatment, with no significant differences observed between treated or untreated HECVRGMbKO cells at any time points. A similar trend was observed in the angiogenic tubule formation assay, where treatment of HECVpEF6 cells with HGF could significantly enhance the levels of tubules formed (mean tubule perimeter, untreated 8087+/− 632 vs HGF treated 13131+/− 988, p = 0.001). Treatment of HECVRGMbKO cells with HGF did not significantly enhance levels of tubule formation (mean tubule perimeter, untreated 7523+/−2458 vs HGF treated 11050+/−1512, p = 0.21).
Conclusions: Targeting of RGMb in endothelial cells appears to reduce their sensitivity to the promotional effect of HGF on cell migration and tubule formation, important traits in the angiogenic cascade. Our data suggests that RGMb may be one molecule involved in the process through which HGF enhances angiogenic potential and targeting this molecule may be a useful strategy in a number of cancer types to interfere with HGF promoted angiogenesis.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-06.
P2-05-10: Brain-Derived Neurotrophic Factor, BDNF, and Its Biological Impact on Vascular Endothelial Cells.
Authors: Jiang WG , Ye L , Yang X , Mansel RE 
Published: June 2012

Abstract
Background: BDNF, Brain-derived neurotrophic factor is a member of the neurotrophin superfamily and is a known growth factor for both central and peripheral nervous systems. While BDNF has been shown to play a role in the development of a number clinical condition including epilepsy, Alzheimer's and Parkinson's disease, it has recently been implicated in human cancers, primarily in neurological related malignancies, as well as ovarian cancer, lung cancer and skin malignancies. We have recently reported a pivotal relationship between BDNF and disease progression and clinical outcome in human breast cancer. Certain members of the neurotrophin family have also been shown to play a role in the regulation of angiogenesis. In the present study, we examined the impact of BDNF on the biological behaviour of vascular endothelia cells.
Materials and methods. Human vascular endothelial cells were used in the present study. A human BDNF expression plasmid was constructed from a cDNA library of normal tissues. Anti-BDNF transgenes were constructed based on the secondary structure of human BDNF and used to knockdown the expression of BDNF from the cells. Vascular endothelial cells with differential expression of BDNF were generated using the expression construct. Cell-matrix adhesion, cell migration and growth were determined.
Results. Human vascular endothelial cells (HECV) expressed very low levels of BDNF, traceable by PCR method. The cells were transfected with BDNF expression plasmid, which allowed establishment of BDNF over-expressing sublines, HECVBDNFexp. Expression of BDNF had a marked influence on matrix adhesion of the endothelial cells (adhesion indices for control and HECVBDNFexp cells being 3.3± 0.83 and 2.18± 0.94, respectively, p=0.01). It is interesting to note that the change of adhesion was likely to involve the focal adhesion (FAK) pathway as a FAK inhibitor, PF573228, had a profound impact on the adhesion of both control and HECVBDNFexp cells. Manipulation of BDNF in endothelial cells had a similar effect on the cellular migration, although to a lesser degree. Conclusions. Brain-derived neurotrophic factor, BDNF, has a profound impact on the biological functions of vascular endothelial cells. This may have implications in the angiogenic process seen in solid tumours.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-10.
P2-09-08: FDG-PET in the Staging of the Axilla in Women with Breast Cancer Treated with Primary Chemotherapy.
Authors: Lao Romera J , Puértolas Hernandez T , Alvarez Alejandro M , Godoy Molias A , Hernandez Garcia A , Millastre Bocos E , Garcia Mur C , Ubieto Laguarda MA , Artal Cortes A , Anton Torres A 
Published: June 2012

Abstract
Background
FDG-PET has proven to be useful during the initial staging of several tumor types. The aim of the present study was to assess the accuracy of this test in the assessment of initial axillary status in patients referred to treatment with induction chemotherapy.
Material and Methods: Women with stage II-IIIA (tumors measuring ≥3cm or positive-staged axillary involvement) to be treated with neoadjuvant Docetaxel-Doxorubicin-Cyclophosphamide (TAC scheme) were included. In every patient a physical exam, MRI, ultrasound-guided FNAB and FDG-PET were performed prior starting chemotherapy. The criteria to consider the axilla to be initially positive were positive surgical staging or type-D pathological response (Miller-Payne) in the axilla. The ability of FDG-PET to predict pathological response in patients with breast cancer was assessed and compared with other routine procedures.
Results: 42 patients (p) were included. Median age was 45 years (30-66). 11p (26.2%) were triple-negative. 2p (4.8%) were Her-2 +. By clinical stage, 13p (30.9%) were IIA, 17p (40.4%) IIB and 12p (28.2%) IIIA. 41p (97.6%) underwent surgery after induction chemotherapy. According to surgical staging 31p (75.6%) were deemed to be N+ from the diagnosis (19p with pathologic N1-3a and 12p with type-D nodal response). PET scan positively detected deposits in the axilla in 26p (83.9%) of those patients compared to 22p (70.9%) with ultrasound-FNAB, 19p (61.3%) physical exam and 14p (45.2%) MRI.
Conclusions: In this study FDG-PET could predict axillary involvement more precisely than other routine staging procedures in these patients submitted to be treated with induction chemotherapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-08.
P2-11-09: EGFR Overexpression in Triple Negative Breast Cancer (TNBC) and Its Association with the Prognosis.
Authors: Liu W , Zhang L , Ma K , Han B , Li S , Xu G , Fan Z , Liu N , Shi A 
Published: June 2012

Abstract
Objective: The aim of this study is to investigate EGFR expression in Triple Negative Breast Cancer (TNBC), and to find the relationship between EGFR overexpression and prognosis of TNBC, further to clarify the significance of EGFR in TNBC and provide valuable information for TNBC therapy.
Methods: 42 triple ***negandection ***ssitive breast cancer patients(studying group) and 40 HER2(3+) breast cancer patients(controling group) who underwent surgery from January 2000 to December 2005 were analyzed. 82 cases of paraffin-embedded specimens were detected by Immunohistochemistry(IHC), fluorescence in situ hybridization(FISH) and polymerase chain reaction(PCR) to investigate the overexpression, amplification and mutation of EGFR gene. The distant-free survival(DFS) and overall survival(OS) of these patients were used to investigate the relationship between EGFR overexpression and the prognosis of TNBC.
Results: 34(43.9%) EGFR overexpression was observed in all cases, while gene amplification was only 7(9.1%) cases. No EGFR gene mutation was found in all cases. Overexpression of EGFR occurring in 57.1% patients in TNBC group and 25.0% patients in HER2 group, and we didn't found any correlation between EGFR overexpression and clinicopathology. 50(61.0%) patients relapsed (TNBC 28,HER2 22) and 27(32.9%) patients died(TNBC 18,HER2 9) were observed during the more than 5 years follow-up. The 5-year DFS was 57.1% and 77.5% respectively, the 5-year OS was 71.4% and 87.5% in TNBC and HER2 groups. In TNBC group, the survival of the EGFR-overexpressing group patients was significantly lower than that of the non-EGFR-overexpressing group patients (p=0.018 for DFS, p=0.026 for OS); In HER2 group, no statistical difference was found (p=0.079 for DFS, p=0.055 for OS).
Conclusions: This study showed that EGFR overexpression increased significantly in TNBC patients, which was no correlation with their clinico-pathological data. EGFR gene amplification was much less frequent than its overexpression. It suggested that EGFR gene amplification may not be the unique mechanism of EGFR overexpression in TNBC. There may be other possible mechanisms and pathways that cause EGFR overexpression. In addition, it may suggest that gefitinib therapy is useless in TNBC patients because we did not find any mutations in the tested exons of TNBC. EGFR overexpression may associate with a poor outcome of TNBC patients which suggest it could be a significant prognostic factor for TNBC patients. EGFR may play important role for molecular-targeting therapy of TNBC.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-09.
P2-12-05: Correlation between Quantitative HER2 Protein Expression and Risk of Brain Metastases in HER2−Positive Advanced Breast Cancer Patients Receiving Trastuzumab-Containing Therapy.
Authors: Duchnowska R , Biernat W , Szostakiewicz B , Sperinde J , Piette F , Haddad M , Paquet A , Lie Y , Czartoryska-Arlukowicz B , Wysocki P , Jankowski T , Radecka B , Foszczynska-Kloda M , Litwiniuk M , Debska S , Weidler J , Huang W , Buyse M , Bates M , Jassem J 
Published: June 2012

Abstract
Background. Patients with HER2−positive breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Within HER2−positive breast cancer tumors, it is possible to resolve a ∼1.5-log range of HER2 protein expression using a novel quantitative HER2 assay (HERmark®). We investigated the correlation between quantitative HER2 protein expression in primary breast cancers and the time to brain metastases (TTBM) in HER2−positive advanced breast cancer patients treated with trastuzumab.
Methods. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER2−positive metastatic breast cancer, defined as 3+ categorical staining by immunohistochemistry (IHC). HER-2/neu gene copy number was subsequently quantified as HER2/CEP17 ratio by central laboratory fluorescence in situ hybridization (FISH). HER2 protein was quantified as total HER2 protein expression (H2T) by the HERmark assay in formalin-fixed, paraffin-embedded primary tumor samples. HER2 variables were correlated with clinical features and TTBM measured from the initiation of trastuzumab-containing therapy.
Results. H2T level (continuous variable) was correlated with shorter TTBM (HR=2.3; p=0.013), whereas HER2 gene amplification by FISH (p=0.28) and continuous HER2/CEP17 ratio (p=0.25) had no significant prognostic impact. The correlation between continuous H2T level and TTBM was confirmed in a multivariate analysis (HR=3.2; p=0.021). Controlling for the competing risk of death from causes other than brain metastases, continuous H2T remained a strong correlate of TTBM (HR=2.7; p=0.0009). In the subset of patients that was centrally-determined HER2 positive by FISH (117 patients), above-median H2T level was significantly associated with shorter TTBM (HR=2.4; p=0.005), whereas this was not true for median FISH/CEP17 ratio (p=0.4). In a multivariate analysis of this subset, continuous H2T (p=0.021) and a time dependent covariate capturing time to non-brain metastases (p=0.0044) were prognostic for TTBM, whereas FISH/CEP17, ER, PgR and grade were not.
Conclusions. These data reveal a strong relationship between quantitative HER2 protein expression levels and the risk of brain relapse in HER2−positive advanced breast cancer patients. Consequently, quantitative assessment of HER2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-05.
P2-12-06: Nomogram To Predict Subsequent Bone Metastasis in Patients with Non Metastatic Breast Carcinomas.
Authors: Lousquy R , Delpech Y , Rouzier R , Gligorov J , Hsu L , Barranger E , Pusztai L , Uzan S , Hortobagyi GN , Coutant C , Ibrahim NK 
Published: June 2012

Abstract
Background
Bone metastasis (BM) is one of the most common sites of distant metastasis for breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of patients at high risk for BM.
Patients and Methods
Medical records of patients with non metastatic breast cancer were prospectively collected for the period between January 1997 and February 2007 at the M.D. Anderson Cancer Center (Texas, USA). A multivariate logistic regression analysis of selected prognostic features was done. Based on Cox proportional hazards regression model, a nomogram to predict BM was constructed and validated in an independent cohort of 579 patients with non metastatic breast cancer at time of diagnosis treated at the Tenon Hospital (Paris, France) between January 2003 and December 2005.
Results: Of 4175 patients with non metastatic breast cancer, 314 developed subsequent BM. Age, T stage, lymph node status, lymphovascular space invasion, breast cancer molecular subtype, adjuvant hormonotherapy were significantly and independently associated with subsequent BM. The nomogram had a concordance index of 0.69 (95% CI, 0.68 to 0.70) in the training set. The validation set showed a good discrimination with a concordance index of 0.65 (95% CI, 0.57 to 0.72). At 3, 5 and 7 years, the nomogram was well calibrated.
Conclusion: We have developed a robust tool that is able to predict subsequent BM in patients with non metastatic breast cancer. Selection of an enriched patient population at high risk for BM will allow to practice individualized therapeutic strategies, an adapted medical supervision and will facilitate the design of trials aiming at its prevention with the use of biphosphonate treatment.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-06.
P2-12-14: Prognostic Value of HER2 Positivity and Negative Hormonal Status in Patients with Small Tumor (&lt;1cm) and Node-Negative Breast Cancer.
Authors: Meattini I , Livi L , Saieva C , Agresti B , Scotti V , Nori J , Sanchez LJ , Vezzosi V , Bianchi S , Cataliotti L , Biti G 
Published: June 2012

Abstract
Introduction. Human epidermal growth factor receptor 2 (HER2) amplification has become the prototype biomarker to develop tailored biological treatment. Many studies suggested that HER2 positivity is an independent predictor of disease recurrence and breast cancer mortality. Trastuzumab has been introduced into clinical practice for high-risk HER2−positive patients who have completed the standard adjuvant treatment.
However, small (&lt;1cm), node-negative tumors remain a subgroup of HER2−positive patients who are currently ineligible for trastuzumab treatment, as clinically they have been deemed to have no requirement for standard adjuvant chemotherapy.
The aim of our analysis was to evaluate the prognostic factors of local and distant recurrence in patients diagnosed with T1a-b, node-negative, HER-2 positive breast cancer.
Materials and methods. A total of 704 patients were diagnosed at Florence University between November 1999 and December 2008 with node-negative, invasive BC that were 1 cm or smaller. Patients with ductal carcinoma in situ, with recurrent BC at presentation and patients that received adjuvant chemotherapy were excluded from analysis.
Results. Mean follow-up was 4.9 years (0.5−10.8 years); we recorded a total of 19 recurrences, including 10 distant recurrences. Mean time to local relapse occurrence was 3.8 years (0.4−7.3 years); mean time to distant metastases diagnosis was 4.4 years (1.4−7.6 years). Among all patients, the recurrence-free survival (RFS) was 93.7%.
The only parameter that emerged as significant predictor of events is the age (p=0.02).
The distant recurrence-free survival (DRFS) rate was 96.5%. Patients who had HER2−positive BC had worse DRFS than patients who had HER2−negative BC (92.0% v 96.9%; p=0.045). In addition to HER2, also HR status was significantly associated with DRFS (p=0.026). Patients who had HR negative status had worse DRFS than patients who had HR positive status (91.4% v 97.4%; p=0.045).
Conclusions. Patients with T1a-b, node-negative, breast cancer have a low risk of distant and local recurrence. Women with HER2−positive and negative hormonal status have a significant risk of distant recurrence and should be considered for anti-HER2 adjuvant therapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-14.