bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fra-1 Expression in In Situ and Invasive Ductal Breast Carcinomas: Association with Worse Prognosis in Invasive Basaloid Tumors.
Authors: Logullo A. , Stiepcich M. , Toledo Osório C. , Pasini F. , Soares F. , Nonogaki S. , Brentani M. 
Published: December 2010

Abstract
Background: Fos-related antigen 1 (Fra-1) is an immediate early gene encoding a member of AP-1 family of transcription factors involved in cell proliferation, differentiation, apoptosis, and other biological processes. A high level of Fra-1 expression is found in various tumors and tumorigenic cell lines, suggesting that Fra-1 may be involved in malignant progression. Objective: Evaluate the significance of Fra-1 expression in breast carcinogenesis and its possible help in sub typing and prognosis of breast carcinomas. Methods: Fra-1 expression was investigated by immunohistochemistry in a Tissue Microarray composed by neoplastic breast tissue from 85 in situ breast carcinomas lesions and 769 invasive ductal carcinomas NOS (IDC), ranging from early stage T1 N0M0 to very aggressive metastatic disease (TxN1-3M1). Positive and negative controls were present in each reaction. Nuclear staining were considered positive. Correlations of Fra-1 expression with other indicators of breast carcinoma prognosis (ER, PR TNM, survival) were analyzed. Results: IDC showed 22.8 % of positivity while in situ lesions maintained a 42.2% of reactive cases. In IDC samples, Fra-1 expression correlated with markers of invasiveness, as Node status, histological grade (P= 0.005 and 0.001, chi-square test) and marginally with presence of metastasis (P= 0.07). Fra-1 was also associated to Cytokeratin (CK) 14 (P= 0.043) and marginally to CK18 and her-2 status (P=0.063 and 0.05), and indirectly to estrogen receptor (P= 0.01). When we select basaloid (CK6 positive, ER negative) cases Fra-1 was associated to worse prognosis (P= 0. 013 - Log Rank test). Conclusions: The data shown here suggest that Fra-1 expression is progressively lost during cancer progression from DCIS to IDC. Fra-1 expression in IDC basaloid tumors confers a worse prognosis. Supported by FAPESP nº 04/04607-8.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2129.
Validation of FOXA1 as a Prognostic Marker in Breast Cancer in a Large Population-Based Tissue Microarray.
Authors: Badve S. , Mehta R. , Jain R. , Nielsen T. , Leung S. , Huntsman D. , Nakshatri H. 
Published: December 2010

Abstract
FOXA (Forkhead box protein A) proteins play major roles in development and differentiation. However, recently, FOXA1 has been identified to play a role in controlling nearly 50% of estrogen receptor target genes and has been deemed as a 'pioneer factor'. It is believed to have a dual role in breast cancer: (1) growth promotion by coactivating ERα and (2) growth inhibition by regulating factors like p27Kip1 and E-cadherin. We studied the expression of FOXA1 in a population based tissue microarray of 4,046 invasive breast cancer cases with a median follow- up of 12.4 years using immunohistochemistry and studied its correlation with estrogen receptor and other clinicopathological variables. The percent positivity (P) and intensity (I) of nuclear FOXA1 expression were multiplied to generate a numerical score (S = P × I) that ranged from 0 to 30. Scores between 0 and 3 were defined as low FOXA1 expression and 4 to 30 were defined as high FOXA1 expression. Variable FOXA1 expression was noted in the 3581 interpretable tumors: none (10.6%), weak (3.5%), moderate (19.3%) and strong (55.1%). High level of FOXA1 expression (FOXA1 score greater than 3) was seen in nearly 86% of the tumors. FOXA1 expression correlated positively with ER (p&lt; 0.0001), PR (p&lt; 0.0001), E-cadherin (p&lt;0.0001), age (p&lt; 0.0001) and negatively with basal subtype (p&lt; 0.0001), Ki67 (p&lt;0.0001), tumor size (p&lt; 0.0001) and tumor grade (p&lt;0.0001). Univariate analyses showed small tumor size (T1 tumors), low grade (Grade I), node negative disease, absence of lymphovascular invasion, ER, PR, Her2, cyclin D1 and Ki67 as independent predictors of better overall survival. Patients with Luminal A subtype breast cancers had better overall survival than those with non-Luminal A subtype breast cancers. FOXA1 is found to be a significant predictor of breast cancer specific survival (p=0.012) and locoregional relapse free survival (p=0.0001). However, FOXA1 did not reach statistical significance for disease free survival (p=0.110) and distant relapse free survival (p=0.147). When stratified by molecular subtypes using IHC, FOXA1 did not show any trend for overall survival. In those treated with tamoxifen, low FOXA1 expression was associated with poor overall survival (p&lt;0.0001). In a subset of ERα-positive breast cancer cases, FOXA1 was a significant predictor of breast cancer specific survival (p=0.012). To summarize, FOXA1 expression in ERα-positive breast cancer is of prognostic significance.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2130.
Correlation of Thymidine Phosphorylase Expression and Lymphocyte Infiltration Detected by Microarray Analysis of Breast Cancer.
Authors: Ruckhäberle E. , Rody A. , Holtrich U. , Engels K. , Gaetje R. , Turley H. , Hanker L. , Solbach C. , Karn T. , Kaufmann M. 
Published: December 2010

Abstract
Background:Thymidine phosphorylase (TP) expression in carcinoma cells has been described as a prognostic factor in breast cancer and a predictive factor for response to 5-FU chemotherapy in some studies. Analysis from prostate cancer reported a correlation of TP with lymphocyte infiltrates of tumors.Material and Methods:Affymetrix microarray data of n=79 normal tissue samples and n=1781 primary breast cancers were analyzed for TP mRNA expression. To study relationships of TP expression with immune cell infiltration of breast tumors we used several metagenes representing certain types of immune cells. Immunohistochemical analysis of TP protein expression using a monoclonal antibody was applied for validation studies.Results:Among normal tissues highest expression of TP mRNA was observed in cells and tissues of the immune system. The profile of TP expression displayed highest correlation with a metagene representing cells of the myeloid lineage as moncytes, macrophages and dendritic cells. Analysis of microarray data from 1781 breast cancer samples suggests that TP expression detected by this method originates mainly from infiltrating immune cells. In line with this observation TP mRNA expression correlated with a immune cell infiltration score determined by pathological inspection of the tumor. However, we also observed a correlation of TP with a metagene of interferone inducible genes which seem to be expressed by carcinoma cells. When we tried to validate these data on the protein level using immunohistochemistry TP expression was demonstrated both in carcinoma cells and stromal cells of the tumor to a varying degree.Discussion:We were able to confirm previous data from prostate cancer that TP expression is strongly correlated to the presence of an intense lymphocyte infiltrate of the tumor for breast cancer. However, microarray data of a bulk tumor sample cannot reveal the cellular origin of TP expression.Conclusion:Thus from this data it is not clear whether lymphocytes of the myeloid lineage either are the actual source of TP expression or induce its expression in carcinoma cells.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2139.
NF-kB Complex Activation and Association of αB-Crystallin and Vimentin with Poor Prognosis in Primary Breast Cancer.
Authors: Sreseli R. , Quinlan P. , Quinlan R. , Bray S. , Kellok D. , Baker L. , Jordan L. , Purdie C. , Thompson A. 
Published: December 2010

Abstract
Background: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a protein complex found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, free radicals, cytokines et.c. NF-kB plays a key role in regulating the immune response and incorrect regulation of NF-kB has been linked to the development of cancer, several inflammatory and autoimmune diseases. The role of NF-kB, its subunits and pathways in breast cancer and in the surrounding stromal tissues remains uncertain. αB-crystallin is a heat shock protein, which function as stress-induced molecular chaperones to inhibit the aggregation of denatured proteins. Previous studies have identified αB-crystallin as a marker of poor prognosis for breast cancer and have suggested that it is an excellent marker for tumours of basal origin. The aim of this study is to examine, for the first time, NF-kB and αB-crystallin, vimentin and HSPs in the same set of breast cancers and stroma and relate this to clinical parameters including outcome.Methods: Tissue Micro Arrays of 0.6mm cores of 246 breast cancers were stained with antibodies to αB-crystallin, vimentin, HSP27 (antibody ERD5) and HSP27 82P and 12 subsequent antibodies for NF-kB (IKKa, Ser276, Ser32/36, 180/181, P52, 1kkygmma, P65, RELB, P100/P52, IkBa, cREL, and P50) and scored using the Quick Score Method.Results: Positive associations have been found between αB-crystallin and IKBA (P=0.001 Fishers exact test (FET)), RELB (P&lt;0.001 (FET)) and SER32/36 (P=0.03 (FET)) whereas Vimentin was positively associated IKBA (P=0.003 (FET)), IKKA (P=0.001 (FET)), P50 (P=0.002 (FET)), RELB (P&lt;0.001 (FET)) and SER32/36 (P=0.01 (FET)). Positive associations have also been found between HSP27 and P50 (P=0.002 (FET)), SER32/36 (P&lt;0.001 (FET)). Antibodies such as 180/181 (P=0.04 Kaplan Meier Log Rank (KM), cREL (P=0.03 (KM)), IKBA (P=0.03 (KM)) and IKKA (P=0.01 (KM)) was associated with good survival and P50 (P=0.002 (KM)) and P65 (P=0.01 (KM)) to poor survival. Expression of αB-crystallin was associated with vimentin (P&lt;0.001 (FET)). Its expression was linked to a low expression of the estrogen receptor. Vimentin expression was associated with estrogen receptor (ER) negative cancers and poor survival (P &lt;0.001 (FET)), P=0.002 (KM Log Rank) respectively). In contrast to αB-crystallin, low expression of HSP27 was associated with low ER and progesterone receptor (PGR).Conclusions: Associations were found between various antibodies within the NF-kB pathway as well as the heat shock proteins αB-crystallin, vimentin and HSP27 with varying implications for overall survival. We aim to clarify the mechanisms to prevent the aggregation of stress-accumulated misfolded proteins and apoptosis resulting better survival.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2143.
Regulators of Mitotic Transition Determine Paclitaxel Resistance In Vitro and Predict Poor Prognosis in Breast Cancer In Vivo.
Authors: Burrell R. , McClelland S. , Juul N. , Downward J. , Szallasi Z. , Szallasi Z. , Swanton C. , Swanton C. 
Published: December 2010

Abstract
We have previously identified 25 kinases that regulate sensitivity to the microtubule-stabilising drug, paclitaxel (Swanton et al., 2007). Silencing these kinases by small-interfering RNA (siRNA), results in resistance to paclitaxel-induced cytotoxicity and dramatic alterations in DNA ploidy, multinucleation and centrosome amplification independent of drug treatment. These data suggest that the molecular pathways that maintain chromosome stability and mitotic fidelity are required for paclitaxel sensitivity. To further address this, we have investigated the function of the 25 kinases in mitosis, using a combination of fixed and live-cell microscopy. Several of these genes regulate mitotic progression and the formation of a bipolar mitotic spindle, and upon depletion, lead to increased rates of chromosome missegregation during anaphase. This supports the hypothesis that mechanisms of chromosomal instability that are common in cancer cells, predispose to paclitaxel resistance. In order to assess the in vivo relevance of these kinases we examined whether lower expression held prognostic power across several breast cancer datasets. Notably low expression of MAST3, CAMK1 and SKAP1 correlates with poor prognosis in breast cancer in vivo (P&lt;0.05). Interestingly, MAST3 and CAMK1 have strikingly similar mitotic phenotypes after silencing; cells arrest in early mitosis and show an increased frequency of anaphase errors that may contribute to chromosomal instability. In summary, we have identified novel regulators of mitotic transition that may be important for maintaining chromosomal stability. These kinases influence taxane sensitivity in vitro and hold prognostic power in breast cancer patients in vivo.ReferencesSwanton, C., Marani, M., Pardo, O., Warne, P.H., Kelly, G., Sahai, E., Elustondo, F., Chang, J., Temple, J., Ahmed, A.A., et al. (2007). Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell 11, 498-512
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2151.
The Hepatitis A Virus Cellular Receptor, HAVcR-1, Reduces the Integrity of Human Endothelial Tight Junctions.
Authors: Martin T. , Harrison G. , Mason M. , Jiang W. 
Published: December 2010

Abstract
Background: Disruption of Tight Junctions (TJ's) in endothelial cells can cause a leaky vascular bed and may therefore lead to vascular spread of cancer cells. Hepatitis A virus (HAV) cellular receptor HAVcR-1, also known as KIM-1/TIM-1, is the cellular receptor for the hepatotropic picornavirus that causes acute hepatitis-A in humans. Although HAVcR-1 is expressed in every human organ, the natural function of HAVcR-1 remains unknown. In the current study, we investigated the location, association and possible functionality of HAVcR-1 in human endothelial cells.Methods: HAVcR-1 protein in human endothelial cells was visualised using immunohistochemistry and mRNA transcript by RT-PCR. A hammerhead ribozyme transgene that specifically targeted human HAVcR-1 was constructed and used to knockdown endogenously expressed HAVcR-1 (HECVHKD); moreover, forced expression was obtained by insertion of a transgene into wild type endothelial cells (HECVHEX).TJ function was assessed using trans-endothelial resistance (TER) and paracellular permeability assays under the influence of HGF (40ng/ml) a cytokine we have previously shown to modulate TJs in human endothelial cells.Results: Human endothelial cells expressed HAVcR-1 at low levels. The location of both endogenous and forcibly expressed HAVcR-1 was at the cell-cell junction, at the region of the TJ. In this study, one of the first to examine the location and binding partners of HAVcR-1, expression of this receptor was targeted to the vicinity of intercellular junctions, via ZO-1, which further was demonstrated to be at the site of the TJ by its co-localisation with ZO-2. This was true of both endogenously and forcibly expressed protein. Moreover, HAVcR-1 was co-precipitated with the regulatory factor Rho C. Although there was no change in function of HECVHEX cells, the TJ function of the HECVHKD cells exhibited significantly reduced response to HGF over 2h (p&lt;0.01). Interestingly, there was no concurrent response in PCP.Conclusion: These results demonstrate for the first time that HAVcR-1 may have a previously undiscovered role in the regulation of TJ integrity in human endothelial cells.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2158.
ER and PR Expression Profile of Circulating Tumor Cells in Metastatic Breast Cancer Patients in Comparison to the Primary Tumor.
Authors: Aktas B. , Mueller V. , Schumacher K. , Tewes M. , Zeitz J. , Kasimir-Bauer S. , Rack B. , Janni W. , Solomayer E. , Fehm T. 
Published: December 2010

Abstract
Background: Introduktion: Several studies have indicated that the expression of predictive markers including ER and PR can change during course of disease. Therefoore, reassesment of of the prediktive markers at the time of disease progression might help to optimize treatment decisions. Metastatic tissue may be difficult to obtain for repeated analysis. In this context, characterization of circulating tumor cells (CTCs) could be of relevance. Therefore, the purpose of the present study was: (1) to reevaluate the ER/PR expression by circulating tumor cells and (2) to compare the hormone receptor status expression profile of CTC with the primary tumor. Materials and Methods: We ecaluated, 166 blood samples from metastatic breast cancer patients at the time of first diagnosis of first metastatic disease or disease progression. All samples underwent immunomagnetic enrichment using the AdnaTest BreastCancerSelect (AdnaGen AG, Germany) within 4 hours after blood withdrawal followed by RNA isolation and subsequent gene expression analysis by reverse transcription and Multiplex-PCR in separated tumor cells using the AdnaTest BreastCancerDetect. CTC were analyzed for the three breast cancer associated markers: GA733-2, Muc-1, Her-2 and β-actin as an internal PCR control. Expression of the estrogen (ER) and progesterone (PR) receptor was assessed in an additional RT-PCR. The analysis of PCR products was performed by capillary electrophoresis on the Agilent Bioanalyzer 2100. Results: The overall detection rate for CTC was 38% (63/166 patients) with the expression rates of 79% for EpCAM (50/63 patients), 77% for MUC1 (49/63 patients), 49% for HER2 (31/63 patients), 23% for ER (15/65 patients) and 11% for PR (7/65 patients), respectively. Comparisons with the primary tumor were only performed in CTC+ patients (n=65). In 41 of 65 (63%) patients with ER+ tumors, CTC were ER- and 38/65 (58%) patients with PR+ tumors did not express PR on CTC. Primary tumors and CTC displayed a concordant ER and PR status in only 34% and 61% of cases, respectively. Conclusion: Most of the CTC were ER/PR-negative despite the presence of an ER/PR-positive primary tumor. The predictive value of hormone receptor status expression profile of CTC for palliative endocrine therapy has to be prospectively evaluated.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3009.
Circulating Epithelial Cells as a Tool for Monitoring Treatment Success of Primary Chemotherapy with Simultaneous or Sequential and without Trastuzumab.
Authors: Camara O. , Kroll T. , Oppel S. , Runnebaum I. , Pachmann K. 
Published: December 2010

Abstract
In spite of ample prognostic markers available in breast cancer, still a considerable proportion of patients with good prognostic markers suffers relapse whereas patients with poor prognostic markers may remain disease free. It would, therefore, be desirable to control, at the individual patient level, whether the applied therapy is effective. Our previous work indicates, that in cancer patients most of the epithelial cells circulating in peripheral blood (CETC) are part of the tumor and that the response of these cells reflects the response of the tumor to the applied therapies.Therefore monitoring the decrease or increase in numbers of these cells providing a unique tool for therapy surveillance was used to monitor neoadjuvant chemotherapy in 26 her2/neu positive breast cancer patients with either IHC3+ or FISH confirmed Her2/neu positive breast cancer. Patients were prospectively analysed for the number of CETC before therapy, before each new cycle of chemotherapy and during maintenance therapy at each visit initially every three months and subsequently at more extended intervals. 1ml of blood was drawn into EDTA vials, red blood cells lysed and the white blood cell pellet stained with FITC-labelled anti-Epcam. Green fluorescent cells were detected by image analysis and dead cells excluded due to red PI fluorescence.After an initial variable reduction of CETC during neoadjuvant chemotherapy, tightly connected to tumor reduction we regularly observed a massive release of cells from the shrinking tumor. Although these cells may not be able to settle in tumors with low metastatic potential, in 4/4 patients with Her2/neu positive tumors who did not receive trastuzumab the number of CETCs further increased after termination of therapy and surgery followed by rapid distant relapse indicating that the cells released in these patients may be highly aggressive with a high potential to settle and grow into metastases.It is, however not clear, whether sequential or simultaneous addition of trastuzumab to chemotherapy is preferential. In our hands 65% of the patients receiving simultaneous trastuzumab showed increasing CETCs and all have suffered relapse whereas all patients with decreasing CETCs are still in complete remission indicating that in the neoadjuvant situation during maintenance therapy an increase in CETC is the earliest indicator of imminent relapse.6/6 patients who received trastuzumab sequentially to the neoadjuvant treatment all showed decreasing numbers with all of them still without signs of disease after 4 years of follow up. Thus, trastuzumab was highly effective in this treatment and even if the tumor cells were not eliminated immediately, trastuzumab contributed to prevent them from settling and growing into metastases and CETC monitoring favours sequential trastuzumab.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3016.
Single Circulating Tumor Cell Detection and Overall Survival in Non Metastatic Breast Cancer.
Authors: Bidard F. , Mathiot C. , Mefti F. , Delaloge S. , Giacchetti S. , Salmon R. , Mignot L. , Sigal-Zafrani B. , Vincent-Salomon A. , Tembo O. , Marty M. , Pierga J. 
Published: December 2010

Abstract
Background: Circulation of cancer cells in the blood is a necessary step of hematogeneous metastasis while circulating tumor cells (CTC) have been reported to have a low metastatic efficiency in preclinical animal models. After a median follow-up of 18 months, we previously reported that CTC detection influences the distant metastasis-free survival (DMFS) in non-metastatic breast cancer (BC) patients (pts) treated by neoadjuvant chemotherapy (NACT) in a multicenter prospective trial. Updated results are presented here, focusing on overall survival (OS) and predictors of metastatic relapse.Methods: In 115 localized BC pts, CTC were prospectively screened (CellSearch) before and after NACT (REMAGUS02). We analyzed their outcome after a median follow-up of 36 months.Results: At baseline, 23% of pts were CTC-positive, but only 10% had more than 1 CTC per 7.5ml of blood. At an individual level, CTC detection before chemotherapy, used as a test to predict metastatic relapse, exhibited a global accuracy of 77%, higher than that of tumor grade (54%), tumor size (57%), lymph node invasion (40%), triple negative phenotype (76%) and pathological complete response (27%). Multivariate analyses for OS and DMFS showed that CTC detection before chemotherapy was a strong independent prognostic factor for both DMFS (p=0.01, RR=5.0, 95%CI[1.4-17]) and OS (p=0.007, RR=9, 95%CI[1.8-45]), along with tumor size and triple-negative phenotype, while post-chemotherapy CTC detection had a lower significance for both endpoints (p=0.07 and p=0.09 respectively).Conclusion: Biologically, the metastatic efficiency of CTC could be higher than previously thought. Clinically, besides confirming our previously reported results, this study shows that CTC detection may become the main prognostic factor in BC pts treated with NACT. Implementing this technique in everyday management might help to identify high-risk pts in whom innovative strategies should be investigated.Supported by PHRC AOM/2OO2/02117, Pfizer inc., Roche, sanofi-aventis.ISRCTN10059974
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3017.