bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison between HER-2/neu, estrogen and progesterone receptors in primary breast carcinomas and matched lymph node metastases.
Authors: Desouki MM , Self SE , Wolff DJ 
Published: December 2010

Abstract
Abstract #3053
Background: HER2, estrogen (ER) and progesterone receptors (PR) are important markers for prognostic and therapeutic implications in breast cancer. Fluorescence in situ hybridization (FISH) and IHC for HER2 gene amplification and evaluation of ER and PR in primary tumor are commonly used methods. However, evaluation of these markers in lymph nodes or distant metastases, which may be more biologically significant, is not that applicable in regular clinical basis. In the current work we compared HER2 (by FISH), ER and PR (by IHC) in matched primary breast carcinomas and lymph node metastases.&#x2028; Design: Formalin fixed, paraffin embedded tissue sections from 39 cases of primary and lymph node metastases were assessed for Her2 (by FISH). Primary tumors of the cases selected were known to be HER2 un-amplified. Also, ER and PR IHC were performed on 36 cases from the same cohort of cases to assess any discrepancy between primary and lymph node metastases of these cases.&#x2028; Result: Out of 39 cases, one case was HER2 amplified in lymph node metastasis compared to un-amplified primary tumor. Eight percent of cases (3/36) were ER negative in LN mets and 6% (2/36) were less strongly positive compared to the positive primary tumors. Nineteen percent (7/36) were PR negative in LN mets in contrast to the matched positive primary tumors. Regarding PR immunoreactivity, 6% (2/36) were PR-positive in LN met compared to their corresponding negative primary tumors.&#x2028; Conclusion: While most matched primary breast tumors and lymph node metastases show concordance in HER2, ER, PR status, we found discordance in a minority of cases. These results suggest the possibility that extension of studies in metastatic breast tumors in parallel with that of primary lesions is informative and can be used to determine further treatment options and predict prognosis in breast cancer patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3053.
Reciprocal regulation of ZEB1 and AR in triple negative breast cancer cells.
Authors: Graham TR , Yacoub R , Liu T , Odero-Marah V , Kimbro K , O'Regan RM 
Published: December 2010

Abstract
Abstract #3054
Introduction: Approximately 60-80% of breast tumors are positive for androgen receptor (AR) and negative for estrogen receptor (ER) and progesterone (PR) (Isola et al. J Pathol. 1993). This suggests that AR may function independently of ER and PR to cross-talk with other factors such as Zinc-finger enhancer binding protein (ZEB1). ZEB1 is a transcription factor involved in the progression of breast cancer primarily through promoting epithelial to mesenchymal transition (EMT). ZEB1 represses the expression of E-cadherin by binding to E-box sequences in the promoter, thus decreasing epithelial differentiation and promotes cell migration.&#x2028; Methods: We established a stable control and ZEB1 knockdown using shRNA in MDA-MB-231 cells, a highly metastatic triple negative breast cancer cell line with mesechymal morphology. The stable cell lines were characterized by immunoblot and RT-PCR analysis and were stimulated with synthetic androgens or an androgen antagonist and cell growth and migration were monitored.&#x2028; Results: ZEB1 regulated the expression of AR in triple breast cancer cell lines. AR promoter contains two E-boxes, which may be critical to the transcriptional regulation of this gene. ZEB1 suppression by stably transfecting shRNA in MDA-MB-231 cells resulted in a decrease of AR mRNA, protein and AR downstream targets. In addition, ZEB1 suppression reduced the protein expression of Cyclin D1 and decreased cell proliferation. Conversely, blockade of AR signaling with bicalutamide resulted in suppression of ZEB1 protein expression in two triple negative breast cancer cell lines. ZEB1 knockdown in MDA-MB-231 cells sensitized the cells to bicalutamide by inducing a greater amount of cell death and a reduction in migration compared to the control cells.&#x2028; Conclusions: Taken together, these results indicate that ZEB1 and AR regulate each other to promote cell growth and cell migration in triple negative breast cancer cells. Inhibition of AR signaling could decrease cell proliferation via ZEB1 in a subset of triple negative breast cancers. The growth of triple negative breast cancers that express ZEB1 and AR could be inhibited by antiandrogen treatment.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3054.
Targeting EGFRs and Src signaling with a modified ectodomain of human EGFR (EBIP) and dasatinib in breast cancer.
Authors: Nautiyal J , Yu Y , Patel BB , Majumdar AP 
Published: December 2010

Abstract
Abstract #3069
It is becoming increasingly evident that many solid tumors including breast cancer show increased activation of several growth factor receptors, specifically EGFR and its family members (EGFRs) as well as c-Src, a non-receptor tyrosine kinase that promote proliferation, inhibit apoptosis and induce metastasis. The EGF-receptor (EGFR) consists of an extracellular ligand-binding domain, a hydrophobic transmembrane region, and an intracellular tyrosine kinase domain. The extracellular or ectodomain of EGFR is essential for ligand-binding and subsequent homo/heterodimerization of the receptor. This raises the possibility that the ectodomain of EGFR could be utilized to inhibit EGFR functions and in turn cellular growth. Recently, we generated an ectodomain of human EGFR (hEGFR), composed of 1-448 amino acids fragment of hEGFR and the 30 amino acid epitope (known as “U” region) of rat EGFR-Related Protein (ERRP) fused at the carboxy-terminal end. The new protein, referred to as EBIP (ErbB Inhibitory Protein), as has been observed for ERRP (Xu et al. Mol. Cancer Ther. 2005 (4): 435-42), inhibits growth of colon and breast cancer cells that express varying levels of EGFR and/or its family members. We hypothesize that inhibition of c-Src and EGFRs will be an effective therapeutic strategy for breast cancer. To test our hypothesis we used Dasatinib (BMS-354825; Bristol-Myers Squibb), a newly developed highly potent, ATP-competitive Src and Abl kinase inhibitor and ErbB Inhibitory Protein (EBIP). Four different breast cancer cell lines (MDA-MB-468, SKBr-3, MDA-MB-453 and MDA-MB-231) expressing different levels of EGFR and/or its family members were used. Both EBIP and dasatinib caused a dose dependent inhibition of growth in all breast cancer cells, but dasatinib was less effective compared to EBIP. However, the combination of Dasatinib and EBIP synergistically inhibited cell growth. In EGFR overexpressing MDA-MB-468 cells, the combination therapy also inhibited invasion through extracellular matrix and decreased colony formation. Induction of apoptosis could be attributed to activation of caspases -9 and -8 and by modulating phosphorylation of anti- and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The combination of Dasatinib and EBIP produced a greater inhibition of EGFR and Src activation and their downstream signaling pathways involving Akt and p44/42 MAPK. Additionally, we observed that EGFR promoter activities as well as transactivation of NFκB in MDA-MB-468 cells were greatly reduced. In conclusion, our data suggest that combination treatment of Dasatinib and EBIP that target EGFRs and Src could be a highly effective therapy for breast cancer than mono therapy, as they are likely to impact several aspects of tumor progression.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3069.
Bone marrow disseminated tumor cells, loco-regional and adjuvant treatment are prognostic factors for loco-regional relapses in early breast cancers.
Authors: Bidard F , Kirova Y , Vincent-Salomon A , Alran S , De Rycke Y , Sigal-Zafrani B , Sastre-Garau X , Mignot L , Fourquet A , Pierga J 
Published: December 2010

Abstract
Abstract #307
Purpose: To study in early breast cancer (BC) patients (pts) if bone marrow (BM) disseminated tumor cells (DTC) are associated with a specific loco-regional dissemination of cancer cells, according to the radiotherapy fields and to the pattern of loco-regional relapses.&#x2028; Patient and methods: BM aspirates were prospectively screened for cytokeratin positive (CK+) cells at primary treatment in stage I-III BC pts. Local recurrence (LR) was defined as recurrence of the breast or chest wall; Regional recurrence (RR) was defined as lymph node recurrence after loco-regional treatment. Irradiation fields, BM DTC status, clinical and pathological variables of the pts were correlated with loco-regional relapse-free survival (LRRFS).&#x2028; Results: BM DTC were detected in 94 out of 621 pts (15%) and were not associated with the axillary lymph node status and other prognostic factors. After a median follow-up of 56 months, 18 pts (2,9%) experienced loco-regional relapses: 15 LR occurred in the RT fields whereas 2 LR and 1 RR were out. 8 of the 18 relapsing pts (44%) were DTC positive (8 LR in the RT fields). BM DTC detection was the only prognostic factor for LRRFS (p=0.0005, OR=5.2 [2.0-13.1]) in multivariate analysis. In BM DTC positive patients, longer LRRFS were observed in those who were given adjuvant hormonal therapy (p=0.03) and RT on supra-clavicular (SCN) and internal mammary (IMN) nodes (p=0.055) (multivariate analysis).&#x2028; Conclusions: BM DTC strongly influence loco-regional relapse in early BC patients. Our data support the hypothesis of a different lymphatic spread of BM DTC positive BC and of a possible re-seeding of BM DTC to the breast. Survival analyses suggest that BM DTC positive patients take advantage of adjuvant hormone therapy but also of adjuvant SCN and IMN irradiation. This observation could be one explanation of the influence of systemic treatment on locoregional relapse and of radiotherapy on distant metastatic dissemination.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 307.
Netrin-1: a promising therapeutic target in metastatic breast cancer. Expression analysis in localized and metastatic breast tumors and preclinical validation.
Authors: Fitamant J , Guenebeaud C , Treilleux I , Tabone E , Chabot S , Bernet A , Mehlen P , Bachelot T 
Published: December 2010

Abstract
Abstract #3075
Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligand. Cells expressing one of these dependence receptors are thus dependent on ligand availability to survive. Such a trait confers on these receptors a tumor suppressor activity by preventing uncontrolled cell proliferation.&#x2028; We have previously shown in breast cancer that gaining autocrine expression of the ligand netrin-1 would represent for cancer cells a selective advantage. Human and murine netrin-1-expressing mammary metastatic cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are used. Such treatments prevent metastasis formation in a syngenic mouse model of lung colonization by a mammary cancer cell line (Fitamant et al., PNAS 2008, vol 105).&#x2028; In order to assess the clinical importance of netrin-1 expression in human breast cancer, we quantified by Q-RT-PCR the mRNA levels of netrin-1 in primary breast cancer biopsies and studied their correlation to pathological and clinical data. We used frozen tumor samples from 120 breast cancer patients treated in our institution between 1993 and 2000. At diagnosis, median age was 50, median tumor size was 40 mm. 11% of the patients had SBR1 tumor, 46% had SBR2 tumor and 43% had SBR3 tumor. Estrogen receptor was positive for 62% of the patients. 17% of the patients were pN0, M0; 71% were pN+, M0 and 12% already had distant metastasis (M+) at time of diagnosis. Although there is no correlation between netrin-1 expression and tumor size, histological SBR grade or hormone receptor status, there is a strong correlation between high netrin-1 expression and the presence of nodal involvement (p=0,007) or distant metastasis at the time of diagnosis (p&lt;0,0001). We hypothesize that high netrin-1 expression allows an early and rapid metastatic dissemination during tumor development. We are currently exploring netrin-1 expression levels at different metastatic sites and are completing survival analysis of our cohort of patients.&#x2028; In parallel, preclinical mice models of xenografts either of human breast cancer cell lines or fresh human breast tumors were used to evaluate netrin-1 targeting strategy. The preliminary results show that disrupting netrin-1 activity appears to be more efficient than a conventional Adryamicin-Cyclophosphamide treatment in decreasing tumor sizes and suppressing lung metastasis.&#x2028; These results support netrin-1 as a marker of metastatic dissemination and as a promising therapeutic target in breast cancer progression.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3075.
Nano-gossypin, a novel cdk2/VEGF inhibitor formulation against breast cancer.
Authors: Nair HB , Veerapaneni P , Sophie DM , Kirma NB , Perla RP , Tekmal RR 
Published: December 2010

Abstract
Abstract #3080
Cyclin-dependent kinases (CDKs) play essential roles in the intracellular control of the cell cycle. The encapsulated therapeutic drug molecules as nanoparticles will offer a sustained delivery of chemotherapeutics in to the target tissue. Nanoparticles enhance the therapeutic efficacy of an encapsulated drug by increased and sustained delivery of the drug inside the cell. Most anticancer drugs are taken up non-specifically by all types of cells, resulting in serious side-effects. Therefore, an ideal delivery carrier for an anticancer drug should be able to transport the drug specifically to cancer cells and release the drug molecules inside the cells to the site of their pharmacological activities. Most of the activity proven natural products were not entered in to the clinical practice due to lack of active formulation and/ or effective targeted delivery systems. In our study we found that gossypin (3,5,7,3',4'-Pentahydroxy-8-O-glucosylflavone) is inhibiting cell cycle progression by inhibiting cyclin dependent kinase-2 (cdk2) when compared with roscovitine, a known cdk2 inhibitor. Gossypin has been shown to induce the accumulation of the tumor suppressor p53, cell cycle arrest in G1 and G2/M phases of the cell cycle, and to induce apoptosis in MCF-7, SKBR-3, and MDA-MB-231 cells with a mean IC 50 of 40uM. Gossypin also found to inhibit vascular endothelial growth factor (VEGF) in vitro. Nanoparticle formulation of gossypin effectively inhibited the growth and colony formation in vitro when compared to parent compound. Gossypin might exert inhibition of tumor cell growth and invasion by cell cycle arrest as well as VEGF induced vascular permeability and tumor neovascularization. The dual mode of action of gossypin may results in highly efficacious inhibition of tumor growth and management of breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3080.
The antineoplasic effect of molecular iodine on human mammary cancer involves the activation of apoptotic pathways and the inhibition of angiogenesis.
Authors: Vega-Riveroll L , Mondragón P , Rojas-Aguirre J , Romero-Romo J , Delgado G , Aceves C 
Published: December 2010

Abstract
Abstract #3082
Breast cancer is the most frequent malignant neoplasia in women. One factor thought to influence the incidence of breast cancer is diet. Japanese women, who have a high dietary intake of iodine (5280 vs 209 µg/day in western population) due to ingestion of seaweed, have the lowest incidence of breast cancer in the world. In normal mammary gland, iodine deficiency is involved in dysplasias, which are reversible with I2 but not with iodide administration. Recent data generated in our laboratory showed that continuous treatment with I2, but not iodide, has a potent antineoplastic effect on tumoral progression in N-methyl-N-nitrosourea-treated virgin rats (50-70%). Also I2 treatment in MCF-7 human breast cancer cells, but not in normal mammary cells (MCF-12F), shows a significant apoptotic effect induced by activation of Bax-caspases and AIF-PARP-1 pathways. Based on these findings, a study of women diagnosed with cancer (mammography and tru-cut biopsy) was initiated. Patients were divided into placebo or I2 (5 mg/day) groups for 2 to 5 weeks before surgery. One day before beginning the I2 treatment and the day of the surgery, urine and blood samples were collected. The day before surgery, a second mammography was obtained. In the tumor samples proliferation (PCNA), apoptosis (TUNEL), and vasculature area (CD-31) were analyzed by immunohistochemistry. Bax, Bcl2, p53, and VEGF proteins were analyzed by Western blot. Circulating TSH and T3 levels were measured by RIA and urinary iodide by HPLC. The results showed that although tumor size did not differ between groups, a significantly lower proliferation and increased apoptotic rate were observed in tumors from women supplemented with iodine. In these tumors the ratio Bax/Bcl2 increased, p53 levels were unchanged, and VEGF levels and vasculature area diminished significantly. Serum TSH and T3 showed no changes in any group, indicating that I2 treatment had not compromised the thyroid status. We propose that I2 supplements should be considered for use in clinical trials of breast cancer therapies. We thank Dr. Jorge Álvarez-Aguirre2,3, Dr. Alonso Gallegos-Corona2, Lic. Concepción Correa-Tinajero3, Alejandro Núñez-Nolasco2,3, and Silvia Serrato-Águila2. This work was partially supported by: PAPIIT-UNAM IN201207, and CONACyT 44976-M and 85952.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3082.
Breast epithelial differentiation is altered in BRCA1mut/+ carriers prior to the onset of cancer and contributes to the basal tumor phenotype.
Authors: Keller P , Gupta PB , Klebba I , Gilmore H , Come S , Schnitt S , Lander ES , Kuperwasser C 
Published: December 2010

Abstract
Abstract #3083
Human breast tumors are broadly divided into either luminal-like or basal-like cancers. This distinction is significant since basal-like tumors are more aggressive and afford a poor patient prognosis relative to luminal-like tumors. For reasons that are unclear, germline mutations in BRCA1 strongly predispose for poor prognosis basal-like tumors. The predisposition for basal-like tumors in BRCA1mut/+ patients could be due to (1) differences in underlying target cell populations between BRCA1mut/+ and BRCA1+/+ women or (2) differences in the genetic mutations arising within a single shared target cell type. This basic question has remained unresolved due to a lack of experimental models in which it can be addressed. We describe here a novel in vivo breast cancer system that enables the generation of tumors by introducing oncogenes into normal breast epithelium derived directly from human breast tissue. This system is unique in that it enables human-derived epithelial cells to be sorted for cell surface markers and transformed without requiring in vitro culture prior to implantation in vivo. Using this experimental system, we show that epithelial cells from BRCA1mut/+ patients give rise to tumors that exhibit multiple features of basal differentiation, in contrast to epithelial cells transformed with identical oncogenes from BRCA1+/+ patients. We show further that non-cancerous epithelial cells from BRCA1mut/+ patients already exhibit atypical differentiation even prior to the onset of cancer, in contrast to cells from BRCA1+/+ women. Remarkably, some of these differences are observable in the context of unperturbed breast tissue obtained from disease-free BRCA1mut/+ and BRCA1+/+ patients. Collectively, these findings show that the increased incidence of basal-like tumors in BRCA1mut/+ patients is a reflection of the altered differentiation of breast epithelial cells in BRCA1mut/+ patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3083.
Is the biology of breast cancer changing? A study of hormone receptor status and grade of breast cancers 1984-1986 and 1996-97.
Authors: Brown SB , Mallon EA , Edwards J , McGlynn LM , Campbell FM , Timothy CG 
Published: December 2010

Abstract
Abstract #3088
Introduction: There has been a significant improvement in breast cancer survival in the UK in recent decades. Changes in the molecular epidemiology of breast cancers may have contributed to this, but the existing evidence may be confounded by heterogeneity of laboratory protocols. This study aimed to re-analyse the molecular profile of breast cancers from two different time periods using archived tissue. Methods: Archived tumour samples from all breast cancer patients at two Glasgow hospitals between 1984-86 and 1996-97 were sought, and linked to clinicopathologic, screening, demographic and survival data. Patients in the 1984-6 cohort would not have been offered mammographic screening but those in 1996-97 would have. Samples were placed in tissue microarrays and underwent immunohistochemistry for ER, PR and Her-2 status with strict standardisation. H&E sections were constructed to assess tumour grade. Statistical analysis included Kaplan-Meier survival analysis and Cox's regression. Results: 900 tumour samples underwent staining. In 1984-86, 8% of tumours were grade 1 and 42.9% grade 3 but in 1996-97 14.9% were grade 1 and 36.8% grade 3 (p=0.009). This effect appeared to be exerted by the presence of screen detected tumours in 1996-97 (p for difference in grade distribution between symptomatic patients between 1984-86 and 1996-97 = 2). In 1984-86 64.2% of tumours were ER positive and in 1996-97 71.5% were ER positive (p=0.042). This did not appear to be a function of the screening programme as there was a significant rise in ER positivity in symptomatic patients between the two cohorts (p=0.024). 44.9% of tumours in 1984-86 and 49.9% of tumours in 1996-97 were PR positive (p=0.181). 21.5% of tumours in 1984-86 and 20.6% of tumours in 1996-97 were Her-2 positive (p=0.772). 5-year survival in 1984-1986 patients was significantly lower than in 1996-1997 patients (p&lt;0.001). When the effect of cohort on survival was adjusted for these changes in ER status and grade, cohort remained a significant independent factor. Conclusions: This study suggests a small but significant rise has occurred in the incidence of ER positive tumours in women in Glasgow. There has also been a shift in grade distribution of tumours, which is likely to be an effect of the NHS screening programme. The changes do not fully explain improvements in breast cancer survival but should be borne in mind when applying the results of clinical trials performed in the past to the women of today.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3088.