bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local Radiotherapy Rescues Responsiveness to Anti-CD137 Immunotherapy in a Mouse Model of Advanced Breast Cancer.
Authors: Pilones K. , Kawashima N. , Formenti S. , Demaria S. 
Published: December 2010

Abstract
BACKGROUND: The benefits of immunotherapy are often hampered by immunosuppressive networks in the tumor microenvironment. Accumulating evidence indicates that local ionizing radiation (IR) can synergize with immunotherapy and improve tumor response.CD137/4-1BB is a co-stimulatory molecule expressed on activated T-cells that provides a survival signal to promote the expansion and differentiation of antigen-specific T-cells. Pre-clinical studies have shown the ability of agonistic anti-CD137 antibodies to enhance anti-tumor immunity. 4T1 is a poorly immunogenic experimental mouse model of metastatic breast cancer. 4T1 cells injected s.c. form a tumor and rapidly spread systemically giving rise to lung metastases that kill the animals. We have previously shown that IR as single modality can delay growth of the irradiated 4T1 s.c. tumors but not extend mice survival.METHODS: BALB/c mice were inoculated s.c. with 4T1 cells on day 0. Treatment with anti-CD137 mAb (200 mg, BMS-469492 from Bristol Myers Squibb) was started on day 7 or 15 and repeated every 3 days for two or three times. For radiotherapy mice were randomized into 4 groups receiving (1) no treatment, (2) IR alone, (3) anti-CD137 mAb and (4) IR+ anti-CD137 mAb. IR was delivered exclusively to the tumor in 2 fractions of 12 Gy at 24 hours interval starting on day 13. Mice were followed for tumor growth and survival.RESULTS: Administration of anti-CD137 mAb to 4T1 tumor-bearing mice starting at day 7 resulted in significant tumor growth delay which correlated with an 8-fold increase in the ratio of intratumural effector CD8 T cells (Teff) to regulatory T cells (Treg) at day 15. In contrast, when administration of anti-CD137 mAb was delayed until day 15 no anti-tumor effect was observed.The median survival of mice (39 days) was not increased by treatment with anti-CD137 mAb or IR used as single modalities (39 days). On the other hand, the combination of IR and anti-CD137 mAb increased survival to 49 days, although no complete tumor remission was observed.CONCLUSIONS:Overall, our studies indicate that with tumor progression mice became resistant to immunotherapy with single modality anti-CD137 mAb. However, a therapeutic effect was seen when anti-CD137 mAb was combined with local radiotherapy. We are currently investigating the mechanisms of resistance to anti-CD137 mAb treatment that develop with 4T1 tumor progression. Accumulation of Treg and myeloid-derived suppressor cells (MDSC) within the tumors likely contribute to resistance to immunotherapy by creating a highly immunosuppressive microenvironment. Identification of these mechanisms will provide new therapeutic targets to improve the response to treatment. Importantly, data support the combination of local radiotherapy with immunotherapy in advanced breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4134.
Elevated Circulating Myeloid Derived Suppressor Cells (MDSC) Are Associated with Inferior Overall Survival (OS) and Correlate with Circulating Tumor Cells (CTC) in Patients with Metastatic Breast Cancer.
Authors: Cole S. , Montero A. , Garret-Mayer E. , Onicescu G. , Vandenberg T. , Hutchens S. , Diaz-Montero C. 
Published: December 2010

Abstract
Background: MDSC acumulation is an important mechanism of tumor escape from immune surveillance and cancer progression. Pre-clinical studies have shown a correlation between tumor progression and MDSC. While we and others have shown that circulating MDSC correlate with clinical stage, to date there are few clinical studies that have explored the correlation of MDSC with metastatic tumor burden or as an adverse prognostic factor. Consequently, the goal of this study was to determine whether levels of MDSC in patients with stage IV breast cancer correlate with tumor burden using CTC and Swenerton Scores (SS) as surrogates for metastatic disease burden, and if circulating MDSC levels were predictive of overall survival.Methods: Flow cytometric analysis was performed on peripheral whole blood from 25 patients with stage IV breast cancer prior to initiation of therapy and at defined intervals during therapy. The MDSC population was defined as lineage-, CD33+, HLA-DR-, CD11b+. CTC (CellSearch®) and MDSC were drawn simultaneously and SS were calculated using a standardized scoring system previously defined and published in the literature. A generalized estimating equation regression model was created and fitted individually for each predictor. OS was defined as time of study enrollment to date of death.Results: Using a generalized estimating equation regression model the percentage of MDSC in peripheral blood was found to have a close correlation with CTC (Pearson correlation 0.62, p=0.0001) and a coefficient of 0.29 (0.14, 0.43 95%CI). The correlation between percent MDSC and SS was not significant (Pearson 0.31, p=0.12). Interestingly, no significant correlation between CTC and SS was noted either. MDSC levels were also found to predict OS in patients with the highest percentages at the first visit having significantly decreased median overall survival [6.8 vs. 19.6 months; p=0.05]Similarly, high MDSC levels at the final blood draw was also found to correlate with significantly shorter median OS [p=0.023].Conclusions. MDSC correlated well with CTC but not SS. High circulating MDSC levels were associated with significantly decreased overall survival in patients with metastatic breast cancer. MDSC appear to be a promising prognostic immunologic biomarker in metastatic breast cancer. Further studies are needed to better define the role of MDSCs in breast cancer progression and may be a useful therapeutic target to enhance the effectiveness of immune based therapies in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4135.
Estrogen Receptor-Mediated Repression of Target Genes: Mechanism of Action, and Biological Significance.
Authors: Oesterreich S. , Jiang S. , Verdin E. , Lee A. , Malik S. 
Published: December 2010

Abstract
Estrogen-bound estrogen receptor (ER) can regulate the transcription of a large number of genes. Although estrogen represses as many genes as it induces, induction has been studied in detail while the repression mechanisms remain largely unknown. In this study we characterized several estrogen-repressed ERα target genes that are directly repressed by estrogen in breast cancer cells. Interestingly, many repressed genes are tumor suppressor genes, playing critical roles in cell cycle inhibition and/or apoptosis. One gene that particularly piqued our interest is Reprimo (RPRM) because of its robust repression in a number of cell lines, and its role as a cell cycle inhibitor. Additionally, it is highly methylated in a variety of cancers including breast cancer and maps to a locus that displays loss of heterozygosity, suggesting that it may be a tumor suppressor gene. As a result, E2-mediated repression of this gene may be a crucial step in the progression of breast cancer. We did show that RPRM decrease (by siRNA) enhances estrogen-mediated S-phase entry, strongly suggesting a biological role of its repression. RPRM was actively and strongly repressed by estrogen and this repression was not due to a quicker turnover of the RPRM mRNA by estrogen. E2-mediated repression of RPRM levels did not require new protein synthesis since it is also repressed in the presence of the translation inhibitor, cycloheximide. We find that estrogen repression of RPRM requires a tripartite interplay between ERα, FoxA1, and HDAC7 as knockdown of these proteins abrogates its repression. Remarkably, silencing of HDAC7 significantly relieved repression of the majority of eleven estrogen-repressed genes tested. Further examination of the interplay between HDAC7 and ERα revealed that HDAC7 can interact with ERα and repress its transcriptional activity in a deacetylase-independent manner. Chromatin immunoprecipitation assays demonstrate that ERα, FoxA1, and HDAC7 are all recruited to a cis-regulatory enhancer (-4.8 kb) in the RPRM gene in the presence of estrogen, which was associated with a release of RNA Pol II from the proximal promoter. Repression requires FoxA1 to be recruited to an epigenetic signature characterized by H3K4 mono- and di-methylation. In summary, we have uncovered a unique requirement for a deacetylase-independent function of HDAC7 in estrogen repression of genes such as RPRM.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4136.
NM23-H2, an ERβ Associated Protein, as a Prognostic Marker in Breast Cancer.
Authors: Hamilton-Burke W. , Speirs V. , Cummings M. , Horgan K. , Shaaban A. 
Published: December 2010

Abstract
Purpose: Endocrine therapy is a well established therapy for estrogen receptor (ER) positive breast cancer. Two ER have been identified but currently only ERα is used in clinical practice. The role of ERβ in breast cancer is less well understood. Two human NM23 genes exist, NM23-H1 and NM23-H2. Several studies have shown an inverse relationship between overexpression of NM23-H1 in breast cancer and disease aggressiveness. NM23-H2, a metastasis suppressor protein, was recently identified as ERβ associated protein in vascular wall of atherosclerotic lesions, but the prognostic significance of this protein and its association with ERβ has not being studied in breast carcinoma. The purpose of this study was to investigate whether NM23-H2 is expressed in breast cancer and its potential clinical implications.Material and Methods: A cohort of 427 patients with diagnosis of primary invasive breast carcinoma between the period of 1994 to 1997 was used for this study. They all were patients diagnosed and treated at the Leeds Teaching Hospitals, UK. Immunohistochemistry was used primarily to identify the expression of NM23-H2 in this study. Regulation of NM23-H2 in vitro in MCF-7 cells was assessed by Western blotting. p&lt;0.05 was considered statistically significant.Results: Patients ages were 27-92 years (median = 58 years, IQ range 47-69 years) with median follow up of 110 months. Tumour size varied from 1 and 130 mm (median=22.7mm, IQ range 14-26mm). Seventy eight percent were invasive ductal carcinoma NST and 11.5% were invasive lobular; 3.9% were special type (tubular, mucinous); and 6.6% were mixed type. Twenty-three percent of the tumours were grade 1, 43.3% were grade 2 and 33.7% were grade 3. Axillary metastases were present in 51% of the cases. NM23-H2 expression was variable between tumours and demonstrated only in the cytoplasm of breast carcinomas. The percentage of staining ranged from 0% to 100% (median 80%).NM23-H2 was strongly correlated with ERβ1 and ERα (p &lt;0.001; correlation coefficient 0.252 and 0.176 respectively). No correlation was found between NM23-H2 with age, size, grade or lymph node status. NM23-H2 when expressed at levels higher than 30% was associated with improved overall survival (p= 0.030). In a multivariate Cox hazard analysis, NM23-H2 overexpression was a significant predictor of better survival independent of tumor grade, lymph node status, size or ERα. MCF-7 cells treated with 17β-estradiol (E2) expressed higher levels of NM23-H2(17.5kDa) compared with serum treated cells.Conclusion: This is the first time to our knowledge that the expression of NM23- H2 in breast cancer and its association with ERβ has been investigated. Our data provide evidence that immunohistochemical overexpression of NM23 H2 is associated with ERβ and ERα in breast cancer and with improved survival. NM23-H2 might be a good prognostic marker in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4148.
QuantiGene 2.0 Assay for ER, PR and HER2 RNA Levels Is a Useful Adjunctive for the Evaluation of ER, PR and HER2 in Breast Cancer.
Authors: Lee A. , Chae B. , Song B. , Jung S. , Yim H. 
Published: December 2010

Abstract
Immunohistochemistry (IHC) for the estrogen receptor (ER) and progesterone receptor (PR) is an established procedure in the routine treatment of patients with breast cancer, primarily to predict responses to hormonal therapy. HER2 IHC and FISH are also recommended to select patients for anti-HER2 based therapy. The IHC method for ER and PR is semi-quantitative and needs standardization. Furthermore, ER and PR RNA levels are continuous variables and quantitative measurement of ER levels can help predict the tamoxifen benefit breast cancer. In this study, the RNA levels of ER, PR and HER2 were measured using the QuantiGene 2.0 assay in formalin-fixed, paraffin- embedded (FFPE) tissue samples from breast cancer (n=40) and compared with conventional ER/PR IHC results and HER2 FISH results. There were no cases of discrepancy in ER status between staining with the SP1 antibody and staining with the 6F11 antibody; however, the ER score was statistically different between them (5.3 ± 3.3 vs. 4.9±3.2, P=0.02). One out of 40 cases (2.5%) showed a false negative result when performed using a 2mm representative tissue sample (TMA), and 1 out of 40 cases (2.5%) showed a discrepant ER status between the results using the Allred scoring system and the fractional scoring system. These results reconfirmed that various factors such as the primary antibodies used, interpretation methods and TMA vs. whole section, influence the results of IHC. When the cut-off values for ER, PR and HER2 RNA levels were 5.0, 7.2 and 50, respectively, the sensitivity, specificity, positive predictive value and negative predictive value of the QuantiGene 2.0 Assay were 96.6%, 90%, 96.7% and 90%, respectively, for ER; 89.7%, 81.8%, 92.9% and 75% for PR, and 83.3%, 96.4%, 90.9% and 93.1% for HER2. The Allred scores for ER and PR were correlated with RNA levels (P=0.046, R=0.32; P=0.00, R=0.61, respectively), and the HER2 FISH ratio was correlated with RNA levels (P=0.00, R=0.76). In conclusion, measuring ER, PR and HER2 RNA levels, which is known to have additional benefits in patient treatment, from FFPE tissue may be a helpful adjunctive in determining the status of ER, PR and HER2 in breast cancer. And the QuantiGene 2.0 assay, which does not require an RNA extraction step, uses FFPE samples, and expensive modern equipment, is easy to perform even in a small scale laboratory.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4153.
Effect of ER/PR Weak Expression on Neoadjuvant Chemotherapy.
Authors: Min S. , Park C. , Lee S. , Jung S. , Lee S. , Kim S. , Kang H. , Kwon Y. 
Published: December 2010

Abstract
Background: Neoadjuvant chemotherapy(NAC) is now a relatively standard treatment for advanced breast cancer. Many reporters suggest that the response rate of NAC on ER/PR positive breast cancer is lower than on ER/PR negative cancer. However, there are few reports regarding the effectiveness of NAC according to expression of ER/PR. The aim of this study is to assess the effect of NAC on ER/PR weak positive breast cancer compared with ER/PR negative and strong positive breast cancer.Patients and Methods: 495 patients who underwent NAC between 2001 and 2008 were included. The patients were treated with variable chemotherapy regimens. We analyzed the response rate to NAC by revewing the preoperative breast imaging study including breast US and postoperative pathologic report. ER/PR expression by IHC were scored as negative, weak positive, intermediate and strong positive. We compared weak positive group with negative and strong positive group. We assessed clinicopathologic characteristics, response rate, disease progression according to ER/PR expression and chemotherapy regimens.Results: There were 165(33.3%) of ER/PR negative, 47(9.5%) of weak positive and 207(41.8%) of strong positive, respectively. Most of preoperative clinical stage was stage IIIA, 166(39.6%). Mean age of patients was 46.7±10.1 year. The pathologic complete response(pCR) was 47(11.2%). In weak positive group, pCR, partial response, stable disease, progressive disease was 9(19.1%), 23(48.9%), 9(19.1%) and 6(12.8%), respectively. There was no significant difference between weak positive group and negative group. However, pCR was less(11(5.3%)) in strong positive group compared with weak positive group. (p=0.004). In patients treated with preoperative anthracycline-based NAC and taxen-based NAC weak positive group was similar to negative group. However, pCR rate of strong positive group was lower than other groups.Conclusion: The clinicopathologic behaviors and effect of NAC on weak positive breast cancer were similar to ER/PR negative breast cancer. Therefore, neoadjuvant chemotherapy might be more effective in ER/PR weak positive breast cancer rather than strong positive breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4157.
DCIS-Associated Myoepithelial Cells Expressing the αvβ6 Integrin Modify Tumour Cell Behaviour: A Predictor of Invasive Progression?
Authors: Jones J. , Allen M. , Thomas G. , Dawoud M. , Vallath S. , Payne S. , Edwards D. , Pennington C. , Marshall J. , Hart I. 
Published: December 2010

Abstract
Ductal carcinoma in-situ (DCIS) now accounts for up to 25% of breast cancer presentations. DCIS will progress to invasive breast cancer in 25-40% of cases, though the mechanisms involved in this progression are poorly understood. Understanding the factors that promote progression to invasive disease is of importance both in terms of developing better prognostic and predictive markers, and also in the development of novel therapies.One of the key features in the progression of DCIS to invasive disease is penetration of the myoepithelial-basement membrane barrier. As well as being a physical barrier myoepithelial cells (MEC) also have been described as tumour suppressors exerting their effects through autocrine and paracrine pathways, but there is evidence that these cells change in DCIS.The integrin αvβ6 is an epithelial-restricted protein, not usually expressed in normal adult tissue, which has been demonstrated to be up-regulated in invasive cancer where it activates TGF-β. Here we show that αvβ6 is up-regulated in the myoepithelial cell compartment of high grade DCIS (∼ 100% in ∼200 cases) especially where invasion also is present. To understand the relevance of this observation we have created a model for DCIS-associated MEC by introducing β6 cDNA into an immortalised MEC line (1089) to create the αvβ6 expressing derivative, β6-1089. Using Transwell assays we demonstrate increased invasive activity of a panel of breast cancer cell lines exposed to conditioned media from β6-1089 cells relative to the control cell line. Using our organotypic assay, to examine invasion in a more physiological manner, we also found that the invasive capacity of MDA-MB-231 cells is enhanced after they are co-cultured with β6-1089 cells. Furthermore, in-vivo experiments demonstrate increased growth of tumour cells injected with β6-1089 MEC compared to control 1089 cells. Expression of αvβ6 de novo in β6-1089 cells caused an increase in MMP9 expression while a chemical inhibitor of MMP9 was able to block the observed increased invasion. Tissue studies revealed a highly significant correlation between MEC expression of αvβ6 and of MMP-9 (p&lt;0.001), supporting these in vitro findings.These results show that up-regulation of αvβ6 expression in MEC from DCIS with associated invasion is a common event and promotes invasion of breast cancer cells through increased elaboration of MMP-9. This suggests expression of αvβ6 by myoepithelial cells may be an important prognostic marker for the progression of DCIS.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4159.
Overexpression or Lack of beta 2-Adrenergic Receptor Correlate with Progression of Breast Cancer.
Authors: Ou Z. , Wang L. , Hong X. , Shen Z. , Shao Z. 
Published: December 2010

Abstract
Background: Recent studies showed that stress can modulate biological behavior of ovarian carcinoma through adrenergic receptors. Since both nonselective beta-adrenergic receptor antagonist propranolol and selective beta 2-adrenergic receptor (b2AR) antagonist ICI 118,551 instead of b1AR antagonist atenolol could eliminate most of the effects, b2AR is accordingly regarded as the key molecule. In this study, we investigated the role of b2AR in breast cancer. Material and Methods: Gene expression of b2AR was analyzed by RT-PCR in human breast cancer cell lines MDA-MB-231, MDA-MB-435, MDA-MB-468, MCF-7, T47D, BT-549, HCC1937, BCaP-37 and normal mammary epithelial-like cell line HBL-100. b2AR cDNA was transfected into MDA-MB-435 cells. Protein level of b2AR was analyzed by immunohistochemistry in clinical samples, including 25 normal human breast or benign disease breast tissues and 202 breast cancer tissues. Results: b2AR was detected in majority of breast cancer cell lines, except for MDA-MB-435, MCF-7 and T47D, and all of normal or benign disease breast tissues. Both nonselective beta-adrenergic receptor agonist norepinephrine (NE) and selective b2AR agonist terbutaline promoted proliferation and invasion of spontaneous b2AR-positive MDA-MB-231 cells and transfectant MDA-MB-435-b2AR cells, these effects were completely inhibited by selective b2AR antagonist ICI 118,551. In the breast cancer patients, 125 samples (61.9%) expressed b2AR weakly or moderately just as normal breast or benign diseases tissue, and 43 (21.3%) presented significantly stronger b2AR expression, while no b2AR staining was found in other 34 samples (16.8%). Higher expression or lack of b2AR were associated with axillary lymph nodes metastasis and poor disease free survival (DFS). Discussion: Based on our preliminary results, the breast cancer patients could be classified into three subgroups: b2AR “normal”, high expression and negative groups. Overexpression or lack of b2AR associated with metastasis and clinical prognosis in breast cancer. Obviously, abnormal expression of b2AR may influence the outcome of breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4165.