bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hedgehog Signaling Pathway Is a New Target of Cancer Stem Cell Therapy for Breast Cancer Patients.
Authors: Tanaka H. , Nakamura M. , Sohzaki M. , Kai M. , Kubo M. , Ohnishi H. , Tanaka M. , Katano M. 
Published: December 2010

Abstract
Introduction: Hedgehog (Hh) signaling pathway is crucial for growth and patterning during embryonic development. We have shown that Hh pathway is constitutively reactivated in human breast cancer (Kubo M et al. Cancer Res 2004). Recently, it has been proposed that only a small subset, termed cancer stem cells (CSCs), posseses tumorigenicity. And, several investigations suggest contributions of morphogenesis pathways including Hh pathway in the maintenance of CSCs. Purpose of this study is to reveal an essential role of Hh pathway in the maintenance of CSCs, and also to reveal a possibility of Hh pathway as a target of CSCs therapy for breast cancer patients.Materials and Methods: A human breast cancer cell line MCF-7 was used. In the present study, we estimated CD44+CD24-/low cells or side population (SP) cells as CSCs. Flow cytometric analysis and sorting were performed to detect and collect CSCs, respectively. To confirm the high tumorigenicity of CSCs, we used a MCF-7 cell xenograft mouse model in NOD/SCID mice. To assess the expression of Hh pathway-related molecules, real-time RT-PCR and fluorescent immunostaining were performed. For blockade of Hh pathway, a Hh inhibitor, cyclopamine, and small interference RNA (si-RNA) against Gli1, a trans-activator of the Hh pathway, were used. We also synthesized peptides with specific affinity for a transmembrane receptor Patched1 (Ptch1).Results: CD44+CD24-/low cells and SP cells in total MCF-7 cells were 10-25% and 1-4%, respectively and these two populations were overlapped with each other. These CSCs were highly tumorigenic, and resistant to anticancer drugs including taxanes.Hh pathway-related molecules such as Shh, a ligand of Hh pathway, and Gli1 were predominantly expressed in CSCs. Cyclopamine and Ptch1 affinitive peptides could suppress the tumorigenicity of CSCs in NOD/SCID mice xenograft transplantation model.Conclusions: Hh pathway at least partly contributes to the maintenance of CSCs in MCF-7 cells. Thus, Hh pathway may be a valuable therapeutic target for CSCs therapy for breast cancer patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1161.
Treatment-Emergent Symptoms and the Risk of Breast Cancer Recurrence in the NCIC CTG MA.27 Adjuvant Aromatase Inhibitor Trial.
Authors: Stearns V. , Chapman J. , Ma C. , Ellis M. , Ingle J. , Pritchard K. , Budd G. , Rabaglio M. , Sledge G. , Le Maitre A. , Elliott C. , Shepherd L. , Goss P. 
Published: December 2010

Abstract
Background: Analyses of adjuvant endocrine therapy suggest that the appearance of new vasomotor or joint symptoms within 3 months of initiating either tamoxifen or aromatase inhibitor therapy predict for lower subsequent recurrence. We hypothesized that new vasomotor or joint symptoms may predict outcomes with anastrozole or exemestane in participants in the ongoing NCIC CTG Trial MA.27. We performed a pooled analysis across treatment arms of the MA.27 trial, to examine the effects of early onset new or worsening symptoms on relapse-free survival (RFS).Methods: 7576 postmenopausal women with early breast cancer were accrued to MA.27, a randomized adjuvant trial of exemestane and anastrozole. The second interim analysis data with a 3 year median follow-up was used for this analysis. The trial's primary endpoint is event-free survival, but for this investigational analysis is RFS, which excludes non-breast cancer deaths. All 7118 participants known to be hormone receptor-positive who received trial therapy, and had no relapse in the first 3 months, were included. The association of vasomotor and joint symptoms with patient characteristics was examined with chi-square tests. Stratified log-rank and stratified univariate and multivariate Cox modeling were used to examine the association of early vasomotor and joint symptoms on disease outcomes.Results: Of 4749 women who were asymptomatic at baseline, 230 (5%) experienced vasomotor or joint symptoms at 3 months. The RFS stratified univariate Cox hazard ratio (HR) for vasomotor or joint-related symptoms was 1.184 (95% CI, 0.675-2.079). When all 7118 women were included, 361 (5%) developed new or worsening symptoms at 3 months. RFS was not statistically significant between the women with or without new symptoms (HR 1.129, 95% CI, 0.708-1.800). Higher T stage was the only factor included in the multivariate Cox RFS model that was associated with new or worsening symptoms (p&lt;0.001).Conclusions: In contrast to prior findings, we did not observe a correlation between early emergence of symptoms and improved RFS. Longer follow-up and analysis by treatment arm and at different time points are required. Additional symptoms and time points will be added to the analysis prior to the meeting. Until further data are available, clinicians should not use treatment-emergent symptoms to counsel their patient whether to continue or change their prescribed medication.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 14.
Alcohol Consumption and Breast Cancer Recurrence and Survival among Women with Early-Stage Breast Cancer.
Authors: Kwan M. , Kushi L. , Weltzien E. , Castillo A. , Caan B. 
Published: December 2010

Abstract
Purpose: To describe alcohol consumption and examine its association with breast cancer recurrence and mortality in the Life After Cancer Epidemiology (LACE) study, a prospective cohort study of early-stage breast cancer survivors.Methods: Patients included 1897 participants diagnosed with early-stage breast cancer between 1997 and 2000 and recruited primarily from the Kaiser Permanente Northern California Cancer Registry. Alcohol consumption (beer, wine, and liquor) was assessed at cohort entry using a food frequency questionnaire. A total of 349 breast cancer recurrences and 332 overall deaths were ascertained after an average follow-up of 5.93 years. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals.Results: A total of 958 women (51%) were considered drinkers (&gt;0.5 g of alcohol per day), and the majority drank wine (90%), followed by liquor (43%), and beer (36%). Drinking ≥6 g/day of alcohol compared to minimal or no drinking (≤0.5 g/day) was associated with an increased risk of breast cancer recurrence (HR = 1.34; 95% CI: 1.00, 1.82) and death (HR = 1.51; 95% CI: 1.00, 2.28). The increased risk of recurrence appeared to be greater among postmenopausal (P for trend = .03) and overweight or obese women (P for trend = .03). No associations were observed for risk of overall mortality and alcohol use.Conclusions: Consuming 3 to 4 alcoholic drinks or more per week might be related to an increased risk of breast cancer recurrence, particularly among postmenopausal and heavier women, regardless of other prognostic factors. While additional prospective studies are needed, these observations suggest that after a breast cancer diagnosis, women should consider limiting their consumption of alcohol.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 17.
A Phenotype-Based Model for Rational Selection of Novel Targeted Therapies in Treating Aggressive Breast Cancer.
Authors: Soldi R. , Gustafson A. , Zhu H. , Wilcox R. , Welm B. , Spira A. , Jeffrey S. , Bild A. 
Published: December 2010

Abstract
BackgroundGlobal transcriptional profiling has facilitated breast cancer research, and has led to analyses of breast cancer phenotypes and clinical outcomes. While gene expression signatures can identify patients with aggressive tumors who require chemotherapy, data that guide drug selection are relatively sparse, generally obtained in clinical trials that treat patients with standard therapies and often limited by small study size. We propose a method that incorporates genomic and in vitro and in vivo preclinical testing of patient tumors to identify optimal and novel therapeutic regimens for individual breast tumors.Methods and FindingsNine independent microarray datasets comprised of 1,723 breast cancer cases were used in a meta-analysis to examine patterns of drug sensitivity predictions. Drug sensitivity signatures were developed based on the Broad Institute Connectivity Map, and applied using binary regression to individual tumor gene expression data. These analyses provide probabilities for each individual tumor's sensitivity to specific drugs, and allows us to identify patterns of drug sensitivity for unique breast cancer phenotypes. We found consistent patterns of drug sensitivity that were specific to individual tumor subtypes. Notably, we discovered that over 80% of basal-like breast cancers were predicted to respond to inhibitors of the phosphatidylinositol 3-kinase pathway and that normal-like tumors were most likely to respond to a heat shock protein 90 inhibitor. Among the more aggressive breast cancer phenotypes, there was a high predicted response to valproic acid (VPA), a histone deacetylase inhibitor. Using a subset of targeted therapeutics that are currently in clinical trials with solid tumors and for which we have drug response signatures, we performed in vitro drug testing on a panel of 18 breast cancer cell lines and found significant correlation between predicted and actual drug sensitivity. Additionally, predicted sensitivity to VPA for specific patient breast tumors was confirmed in vitro and in vivo, using 3-D primary cell culture and orthotopic xenografts generated from the same human tumors for which the predictions were made. These studies highlight VPA as an effective therapy for aggressive breast cancer tumors, and underscore the suitability of our genomic approach to identify optimal targeted therapeutic strategies for women with breast cancer.ConclusionsWe provide a drug sensitivity prediction model using primary tumor gene expression profiles and offer preclinical examples of drug response based on this model. This approach can be used to personalize drug therapy for patients with breast cancer. This will hopefully improve clinical responses for patients while sparing them toxicity from agents that will have no effect on their tumors.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2007.
Estrogen Receptor α Phosphorylation on Serine 305, p21-Activated Kinase 1 and Tamoxifen Response in Postmenopausal Breast Cancer.
Authors: Bostner J. , Fornander T. , Skoog L. , Nordenskjöld B. , Stål O. 
Published: December 2010

Abstract
Background: Tamoxifen is an adjuvant treatment for estrogen receptor (ER) positive breast cancer. Despite high response rates, resistance is a widespread problem. p21-activated kinase 1 (Pak1) is suggested to phosphorylate the serine 305 residue of the ERα and influence the response to tamoxifen. We aimed to investigate the combination of Pak1 and pERαser305 in relation to treatment prediction and prognosis.Material and Methods: We examined Pak1 and pERαser305 protein by immunohistochemistry in a series of 912 tumors from node negative postmenopausal breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment.Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity while nuclear Pak1 and pERαser305 correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pERαser305 predicted reduced response to tamoxifen in patients with ERα-positive tumors (tamoxifen versus no tamoxifen, HR=1.33; 95% CI, 0.42-4.2, p=0.63), whereas patients lacking this combination of protein expression in the tumor benefitted significantly from tamoxifen (HR=0.42; 95% CI, 0.29-0.61; p&lt;0.0001). Similar non-significant trends were detected in analyses of the two proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR=1.80; 95% CI, 1.18-2.76, p=0.006) and breast cancer mortality (HR=2.02; 95% CI, 1.16-3.52, p=0.014) for patients randomized to no adjuvant treatment.Discussion: Our results suggest that patients with tumors expressing nuclear Pak1 and nuclear pERαser305 in combination represent a subgroup in which tamoxifen treatment is insufficient. Our findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus. In addition, the Pak1-ER pathway may be of interest as drug target in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2013.
An Exploratory Study of the Biological Activity of Sunitinib as a Component of Neoadjuvant Therapy for Breast Cancer.
Authors: Miller K. , Estes M. , Perkins S. , Schneider B. , Matei D. , Storniolo A. , Ingram D. , Yoder M. , Kern K. , Sledge G. 
Published: December 2010

Abstract
Background: The neoadjuvant setting provides an ideal opportunity to explore the impact of sunitinib alone and in combination with paclitaxel on the functional status of tumor vasculature as indicated by changes in tumor interstitial pressure (IFP) and circulating progenitor cell (CPC) subsets.Methods: Patients(pts.) with newly diagnosed stage Ic-IIIc breast cancer were treated with sunitinib monotherapy (100 mg Day 1; 37.5 mg D2-14) prior to the initiation of paclitaxel (80 mg/M2 D1,8,15 every 28 days x 4 cycles) with sunitinib (25 mg/d). IFP and CPC subsets were assessed at baseline and after sunitinib monotherapy. IFP was measured in three separate areas of the tumor using a micropressure transducer catheter; mean and highest IFP recorded were analyzed. Improvements in poly-chromatic flow cytometry allowed distinction of pro-angiogenic (pCPC = Live/AC133+CD34bright/CD31+CD45dim\), from non-angiogenic (nCPC = Live/AC133-CD34bright/CD31+/CD45dim\), CPCs that cannot be quantified separately using previously reported protocols1. Baseline CPC subsets were also compared to age and gender matched healthy controls.Results: From July 2008 to May 2009, 14 pts were enrolled; baseline and post-sunitinib IFP and CPC data are available for 12 and 11 pts respectively. The median age was 48 (range 32-69). Mean pretreatment tumor diameter was 3.2 cm. Sunitinib monotherapy was generally well tolerated; two patients developed grade III toxicities including hypertension (n=1) and hand-foot syndrome (n=1). Sunitinib significantly decreased mean IFP (18.87 mmHg vs. 6.38 mmHg; p=0.002); similar results were obtained when only the maximum IFP was considered (22.32 mmHg vs. 8.36 mmHg; p=0.003). pCPC frequency was not different between pts and healthy controls (0.099% vs. 0.076%, p=0.24) but the p:nCPC ratio was significantly higher in pts compared to healthy controls (3.26 vs. 1.46; p=0.001) suggesting a shift toward vascular damage and/or active angiogenesis. Both pCPC frequency (0.099 vs. 0.022; p=0.001) and p:nCPC ratio (3.26 vs. 0.78; p=0.001) significantly decreased after sunitinib monotherapy. Analysis of paclitaxel + sunitinib is too early (n=4).Conclusion: Sunitinib, through its effects on VEGF-mediated vascular permeability, markedly reduces tumor IFP. In addition sunitinib profoundly reduces pCPCs that are thought to be important for angiogenesis in human cancers. Accrual is ongoing (planned N=40). Analysis of IFP and CPC subsets after paclitaxel + sunitinib as well as additional correlates will be presented.1 Duda et al. (2007). Nat. Protocol 2, 805-810.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 202.
TIMP-1 Status Measured by Immunohistochemistry in 268 ER Positive Postmenopausal High-Risk Breast Cancer Patients Treated with Adjuvant Tamoxifen: Association to Recurrence Free Survival.
Authors: Bjerre C. , Knoop A. , Lyng M. , Ditzel H. , Brünner N. , Bartels A. , Laenkholm A. 
Published: December 2010

Abstract
Background: A proportion of ER positive breast cancer patients do not benefit from adjuvant tamoxifen treatment. Tamoxifen has been shown to induce apoptosis in human breast cancer cells in vitro and Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) protects cancer cells against apoptosis. We therefore raised the hypothesis that ER positive breast cancer cells with high TIMP-1 immunoreactivity would show reduced benefit to tamoxifen treatment.Material and methods: Tumor tissue from 268 high-risk postmenopausal ER positive breast cancer patients was used for this study. All patients underwent surgery for primary invasive breast cancer. The majority of the patients were lymph node positive: 92% (246/268). Patients were allocated to 1, 2 or 5 years of adjuvant tamoxifen as mono-therapy. Recurrent disease was diagnosed in 33% (89/268) of the patients. Median time to recurrence was 3.1 years and the median time of follow-up was 12.4 years. Archival formalin-fixed and paraffin-embedded primary tumor tissue was used to generate tissue microarrays comprising two, 2 mm cores from each tumor. TIMP-1 immunoreactivity was evaluated using the mouse monoclonal antibody (clone VT7) raised against recombinant human TIMP-1. This antibody exclusively reacts with TIMP-1. A central assessment of TIMP-1 status was performed. Tumors were analysed by bright field microscopy and scored semi-quantitatively as 0 - 3 with regard to the number of stained tumour cells and intensity of the staining. An index combining the number of positive tumor cells and staining intensity was created: low (0-2), median (3-4) and high expression (5-6).Results: IHC was successfully performed in 266 cases. TIMP-1 IHC negative cases were observed in 39% (105/266) of the tumors and 61% (161/266) were TIMP-1 IHC positive. The index combining the number of positive tumor cells and staining intensity showed low expression in 59% (157/266), median expression in 24% (65/266) and high expression in 17% (44/266) of the tumors. TIMP-1 negativity and low TIMP-1 index showed no significant association with tumor grade, tumor size or lymph node status. When performing Kaplan-Meier plots, TIMP-1 expression was not significantly associated with recurrence free survival in univariate analyses (p = 0.1).Conclusion: This study did not confirm our hypothesis that TIMP-1 immunoreactivity in ER positive breast cancer cells are associated with reduced benefit from adjuvant tamoxifen treatment. This is partly in contrast with prior studies on endocrine therapy of metastatic breast cancer (Lipton et al 2008) where high serum TIMP-1 was associated with reduced response to endocrine therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2025.
Evaluation of Changes in Plasma Protein Profiles during Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer Using MALDI-TOF/MS Procedure.
Authors: Mazouni C. , Baggerly K. , Hawke D. , Tsavachidis S. , André F. , Buzdar A. , Martin P. , Kobayashi R. , Pusztai L. 
Published: December 2010

Abstract
Background: Comparison of protein profiles of the plasma before chemotherapy and after completion of neoadjuvant chemotherapy may reveal tumor markers that could be used to monitor tumor response.Patients and Methods: We examined matching pre- and post-treatment serum samples 39 HER2-postive breast cancer patients (n=78 samples) who all received 6 months of preoperative chemotherapy with or without trastuzumab in the context of a randomized clinical trial. Serum was analyzed with an Applied Biosystems 4700 Proteomics Analyzer matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometer. Samples were grouped and pooled into those who achieved pathological complete response (pCR, n=20) and those who had residual disease (RD, n=19). We compared matching baseline and post-chemotherapy/pre-surgery samples separately in both response groups and also compared baseline samples between the two response groups.Results: MALDI-TOF analysis revealed a total of 2329 and 3152 peaks in pooled samples of cases with pCR and RD, respectively. A total of 32 peaks were differentially expressed between base line and post-chemotherapy pCR samples and 643 peaks in cases with RD (false discovery rate ≤ 20%). A total of 8 differentially expressed proteins were identified in the before- and after-chemotherapy samples from their peptides after digestion and LC-MALDI-TOF/TOF. These included 4 AFM, C3, hemopexin, SAP in pCR samples and AP1, hemopexin, Complement B, amyloid P component in the RD group.Conclusion: Our study suggests that MALDI mass spectrometry may be used to detect differences in baseline serum profiles of patients who are highly sensitive to chemotherapy and those who are less sensitive. Also, changes occur in the serum during chemotherapy and this may offer the possibility of monitoring response to treatment in the future.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2037.
Predictors of Response to Exemestane as Primary Endocrine Therapy in Estrogen Receptor-Positive Breast Cancer.
Authors: Yoshimoto N. , Takahashi S. , Ito Y. , Yamashita T. , Ando Y. , Toyama T. , Sugiura H. , Kobayashi S. , Fujii Y. , Iwase H. , Yamashita H. 
Published: December 2010

Abstract
Endocrine therapy is the most important treatment of choice for estrogen receptor-positive breast cancer. Potential mechanisms for resistance to endocrine therapy involve estrogen receptor (ER)-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine therapy resistance, particularly resistance to aromatase inhibitors, have not been clearly established. Sixteen postmenopausal patients with ERΑ-positive primary breast cancer were treated daily with 25 mg of exemestane (an aromatase inhibitor) for 6 months. Expressions of ERΑ, ERΒ, progesterone receptor (PgR), androgen receptor (AR), AIB1, aromatase, EGFR, HER2, Ki67, cyclin D1, p53, Bcl2, Stat5 and IGFBP5, and phosphorylations of ERΑ serine (Ser) 118, ERΑ Ser167, Akt Ser473 and p44/42 MAPK threonine (Thr) 202/ tyrosine (Tyr) 204 were examined by immunohistochemistry on pretreatment tumor biopsies and posttreatment surgical specimens. Analyses were made to test for correlations with response to exemestane. Of the 16 patients, 7 responded and 9 retained stable disease. High-level expression of AIB1 and phosphorylation of Akt Ser473 were significantly associated with a better response to exemestane, suggesting that these factors could be considered as predictors of exemestane response. Expressions of ERΑ, ERΒ, PgR, aromatase, Ki67, cyclin D1 and p53, and phosphorylations of ERΑ Ser118, ERΑ Ser167 and p44/42 MAPK Thr202/Tyr204 were decreased, whereas expressions of Stat5 and IGFBP5 were increased in posttreatment specimens compared to the values in pretreatment biopsies. Thus, the analysis of factors involved in the estrogen-dependent growth-signaling pathways may be useful in identifying patients responsive to exemestane.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2041.