bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Antiproliferative Effect of Calcitriol on Breast Cancer Cell Lines Depends on Vitamin D Receptor Status and the Expression of Prostaglandin Metabolizing Enzymes.
Authors: Thill M. , Friedericke H. , Katharina K. , Dittmer C. , Dorothea F. , Klaus D. , Michael F. , Becker S. 
Published: December 2010

Abstract
Background: Both first studies in prostate cancer and our results in breast cancer suggest a link between vitamin D and prostaglandin metabolism. There is a growing body of evidence that COX-2 expression is a fundamental step in breast cancer pathogenesis acting through prostaglandin-dependent and independent mechanisms. The antiproliferative effects of calcitriol (1,25(OH)2D3) mediated via the vitamin D receptor (VDR), render the biologically active form of vitamin D a promising target in breast cancer therapy.Materials and methods: The expression of VDR, COX-2 and 15 PGDH was determined by Western blot in MCF-10F cells, a human benign epithelial cell line, in MCF-7 cells, a moderate invasive and in MDA-MB-231 cells, a highly invasive breast cancer cell line. Measurement of basal PGE2 secretion was performed with ELISA. The influence of calcitriol on cell proliferation was determined by 5-bromo-2-deoxyuridine (BrDU) incorporation (BrDU ELISA). In addition we examined the effect of calcitriol on COX-2, 15 PGDH and VDR protein levels compared to untreated cells.Results: After 72 hours the proliferation of MCF-10F cells was dose-dependent inhibited to 0.83± 0.1 by 1 nM calcitriol. Concurrently, we observed a reduction of COX-2 expression to 0.63± 0.05 as compared to the untreated control group, but we also found a reduction of 15 PGDH to 0.73± 0.16. These effects were associated with a higher expression of VDR to 1.64± 0.16. Interestingly, MCF-7 cell growth was reduced to 0.52± 0.04 by 10 nM calcitriol and to 0.7± 0.06 by 1 nM. These effects do not seem to be associated with COX-2 and 15 PGDH and are independently of VDR. VDR was detected neither in stimulated nor in unstimulated cells. A PGE2 secretion could not be detected by ELISA. In contrast, we found no effect on cell growth, COX-2 and 15-PGDH expression of the MDA-MB-231 cells when treated by calcitriol (10 nM and 1 nM). Although PGE2 was synthesized 2.3-fold more by MDA-MB-231 cells than MCF-10F cells; the COX-2 expression was consistent with the MCF-10F cells, but 15-PDGH was expressed about 50 % less. As we have shown in MCF-7 cells, an expression of the VDR could not be detected.Conclusions: The growth inhibiting effect of calcitriol in MCF10F cells is associated with the increasing expression of VDR. and a remaining question is whether the loss of VDR goes along with the invasiveness of the breast cancer cell lines. Additionally, we suggest that the invasiveness of the breast cells is abetted by the increased COX-2 expression (MCF-7) or by the decreased expression of 15 PGDH (MDA-MB-231). These results suggest even more a link between vitamin D and prostaglandin metabolism and therefore a possible synergism between COX-2 inhibition and calcitriol in breast cancer cells.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5155.
Genetic Characterization of Columnar Cellular Lesions and Atypical Ductal Hyperplasia of the Breast.
Authors: Ellsworth R. , Weyandt J. , Fantacone-Campbell J. , Deyarmin B. , Ellsworth D. , Hooke J. , Shriver C. 
Published: December 2010

Abstract
Aims: Columnar cell lesions (CCL) and atypical ductal hyperplasia (ADH) frequently coexist and share molecular changes with in situ and invasive components, suggesting that CCL and ADH may be precursors to breast cancer. These conclusions are, however, largely based on studies examining CCL and/or ADH from patients diagnosed with more advanced disease. Thus, we assessed allelic imbalance (AI) in pure CCL or ADH specimens to characterize molecular changes in early breast lesions.Methods and results: DNA samples were obtained from laser microdissected lesions from CCL with (n=42) or with ADH (n=31) without concurrent in situ or invasive disease. AI was assessed at 26 chromosomal regions commonly altered in breast cancer. The average AI frequency was 6.2% (range 0-20%) in CCL and 6.1% (range 0-25%) in ADH with no significant difference in levels of AI between CCL and ADH. The highest levels of AI were on chromosomes 8q24 and 17q21 in ADH (23%) and CCL (15%), respectively.Conclusions: In conjunction with low overall levels of AI, chromosomal alterations that characterize low- and high-grade in situ and invasive disease were not frequent in pure CCL and ADH. Thus, pure lesions are not genetically advanced and are molecularly distinct from synchronous lesions.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5156.
“VISA” Nanoparticles to Breast Cancer.
Authors: Xie X. , Deng W. , Yang M. , Tang J. , Wang X. , Wei W. , Xie Z. , Xiao X. , Liu P. , Lang J. , Hung M. 
Published: December 2010

Abstract
Development of cancer gene therapy has been hampered by the fact that there are no effective cancer-specific expression vectors available, which is critical for improving therapeutic efficacy and reducing toxicity in clinics. To overcome this problem, we recently developed a safe and effective strategy fro targeting a potent pro-apoptotic gene (BikDD) to the pancreatic tumors (Xie et al. Cancer Cell, 2007). A VISA system (VP16-Gal4-WPRE integrated systemic amplifier) was engineered by using the two-step transcriptional amplification (TSTA) system and the posttranscriptional regulatory element of the woodchuck hepatitis virus (WPRE). The VISA system can boost the activity of cancer-specific promoters by an average of 600 folds compared to their basal levels. C-VISA (CCKAR-VISA) nanoparticles transcriptionally targets transgene expression effectively to pancreatic tumors in vivo. C-VISA-BikDD nanoparticles was shown to be highly effective in reducing tumor burden and increasing animal survival rate in orthotopic pancreatic cancer models which is moving into clinical trials at University of Texas M.D. Anderson Cancer Center, USA. In the current study, we identified hTERT(human telomerase reverse transcriptase), ß-cateinin, claudin-4, and FASN (fatty acid synthase) promoters as breast cancer-selective promoters, and amplified their activity to hundreds of folds greater by the “VISA” system without loss of their specificity. We further demonstrated significant antitumor activity of targeted BikDD expression driven by nanoparticles of the hTERT-VISA-BikDD vectors in Her-2-negative and -positive breast cancer cell lines and in multiple breast cancer models of living imaging by the Xenogen IVIS imaging system with limited toxicity. In addition, treatment with hTERT-VISA-BikDD nanoparticles plus lapatinib or produces evident combinational therapeutic efficacy, which is likely due to the ability of lapatinib to promote apoptosis of Her-2-overexpressing breast cancer cells. Thus, our newly developed hTERT-VISA-BikDD nanoparticles are an innovative strategy for targeted antitumor effects of both Her-2-negative and Her-2-positive breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5159.
Genetic Contribution of GADD45A to Susceptibility to Sporadic and Non-BRCA1/2 Familial Breast Cancers: A Systemic Evaluation in Chinese Populations.
Authors: Yu K. , Di G. , Shao Z. 
Published: December 2010

Abstract
GADD45A is a candidate breast cancer susceptibility gene because its product participates in DNA repair and it is a downstream gene of p53 and BRCA1, both of which are breast cancer susceptibility genes. The genetic contribution of GADD45A to sporadic and familial breast cancer is still ambiguous. We screened germline mutation of GADD45A in 185 non-BRCA1/2 familial breast cancer patients, but no deleterious mutation was found. Seven single-nucleotide-polymorphisms were identified in a sub-sample. Five common variants (minor allele frequency (MAF)&gt;10%) were genotyped for association analyses to scrutinize the relationship between breast cancer and polymorphisms in GADD45A in two independent population sets. In the first case-control study, a comparison of genotype frequencies between sporadic breast cancer patients and controls indicated the CT/TT-genotypes of +1506C&gt;T and CG/CC-genotypes of +3204G&gt;C were associated with decreased breast cancer risk (adjusted odds ratio (OR), 0.77; 95% confidence interval (CI), 0.62-0.96; and adjusted OR, 0.71; 95%CI, 0.57-0.88, respectively) compared with their wild-type homozygotes. A common hyplotype CGTCC was also associated with reduced risk (P=1.0×10-4). In a second familial breast cancer patient-based case-control study, although +1506C&gt;T and +3204G&gt;C failed to be validated, the haplotype CGTCC showed a borderline significance. Notably, the combined P-values were robust for +3204G&gt;C (P=3.1×10-4) and CGTCC (P=1.6×10-5). Moreover, CGTCC was correlated with a higher GADD45A expression in normal breast tissues. In conclusion, although germline mutation of GADD45A is not common in familial breast cancer patients, polymorphisms/haplotypes in GADD45A contribute to breast cancer risk, at least to sporadic breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5163.
Gene Expression Profiling of Phenotypically-Defined Hormone-Receptor Positive Breast Cancer: Evidence for Increased Transcriptional Activity of the Insulin Growth Factor Receptor Pathway and Other Pathways.
Authors: Sparano J. , Gray R. , Goldstein L. , Childs B. , Brassard D. , Bugarini R. , Rowley S. , Baker J. , Shak S. , Badve S. , Baehner F. , Kenny P. , Perez E. , Shulman L. , Martino S. , Sledge G. , Davidson N. 
Published: December 2010

Abstract
Background: Approximately 70% of all breast cancers are hormone receptor (HR)-positive tumors that are sensitive to endocrine therapy, but some patients have recurrence despite adjuvant endocrine therapy. We performed an exploratory analysis of gene expression in HR-pos operable breast cancer in order to identify potential novel therapeutic targets and biomarkers associated with recurrence. Methods: RNA was extracted from primary tumor samples obtained from 776 patients with stage I-III breast cancer treated with adjuvant chemohormonal therapy in trial E2197 (JCO 2008; 26: 4092-4099), of whom 458 had HR-pos disease (defined in a central lab; JCO 2008; 26: 2473). We evaluated RNA expression patterns (by quantitative RT-PCR using a panel of 371 rationally selected genes) in HR-pos cases compared with the HR-neg cases using weighted T statistics, and determined which genes in the HR-pos, HER2-neg group were associated with recurrence (using Cox proportional hazards model score test, Korn's adjusted P value &lt;5% with false discovery rate &lt; 10%).Results: The top 10 genes exhibiting significantly higher expression in the HR-pos group (p≤ 6.17e-160) included ESR1 plus 5 estrogen regulated genes, confirming our approach of evaluating gene expression in phenotypically-defined subsets. Other pathways that exhibited higher expression in the HR-pos group (among the 40 top genes with higher expression, p&lt;8.66e-53) included the insulin growth factor (IGF) (IRS1, IGFR1, IGFB2), Ras (RhoB, RhoC, RAB27B, GGPS1), and HER pathways (ERBB2, ERBB3, ERBB4), and other genes involved in apoptosis (BCL2, BCL2L1, BAG1, NME6, BBC3), signaling (MAPK3, SEMA3F, RXRA), mismatch repair (MSH3), cell cycle regulation (CCND1), stress response (HSPB1), and tumor suppressor genes (TP53BP1, APC). These patterns were similar in HER2-pos cases. Pathway analysis (Ingenuity) revealed substantial interconnectivity among these genes, especially between IGFR1, ERB2/3/4, MAPK3, BCL2, and CCND1, but not RhoB/RhoC. Genes for which increased expression was associated with increased recurrence included those associated with proliferation (TOP2A, AURKB, PLK1) and apoptosis (BIRC5 - survivin).Conclusions: This exploratory analysis reveals several pathways that exhibit higher transcriptional expression in HR-pos disease, some of which are also associated with a higher risk of recurrence, suggesting that they may be potential therapeutic targets. This provides rationale for testing agents currently available in the clinic that inhibit the IGF and other pathways.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5165.
Should Liver Metastases of Breast Cancer Be Biopsied To Improve Treatment Choice?
Authors: Fumagalli L. , Curigliano G. , Bagnardi V. , Locatelli M. , Aurilio G. , Della Vigna P. , Monfardini L. , Giudici S. , Viale G. , Toppo L. , Goldhirsch A. 
Published: December 2010

Abstract
Background: Decision making on systemic treatment of women with metastatic breast cancer is based on features like estrogen receptor (ER), progesterone receptor (PgR), and HER2 status assessed on the primary tumor. We evaluated the concordance of receptor status between primary tumor and liver metastases and estimated the potential change of these pathological features and its impact on treatment choice.Materials and methods: We retrospectively analyzed a database including ultrasound guided liver biopsies performed from 1995 to 2008. All tissue samples, both from primary tumor and liver metastases, were analyzed for ER, PgR and HER2 status. Clinical and biological data were obtained from medical charts (including treatments before and after liver biopsy). Differences between proportions were evaluated using the Pearson chi-square test.Results: We identified 215 consecutive patients with matched primary and liver tissue samples. Median time from primary diagnosis to liver biopsy was 4.1 years (range 0-18.3 years). Changes in ER status were observed in 38/215 patients (17.7%). 15/47 patients (31.9%) changed from ER negative to positive and 23/168 patients (13.7%) changed from ER positive to negative [p= 0.0038]. Changes in PgR status were observed in 111/215 patients (51.6%). 16/74 patients (21.6%) changed from PgR negative to positive and 95/141 patients (67.4%) from PgR positive to negative [p &lt;0.0001]. 11/41 patients (26.8%) changed from ER and PgR negative to ER or PgR positive [Group A] and 25/174 patients (14.4%) changed from ER or PgR positive to ER and PgR negative [Group B] [p=0.054]. In the Group A the treatment of 4/11 patients (36.4%) was changed after biopsy: 2/4 started endocrine treatment (HT) and 2/4 stopped it. In Group B the treatment of 16/25 patients (64%) was changed after biopsy: 15/16 stopped HT. Changes in HER2 status were observed in 19/131 patients (14.5%): 5/93 patients (5.4%) changed from HER2 negative to positive and 14/38 patients (36.8%) changed from HER2 positive to negative [p= &lt;0.0001]. In this group 5/5 patients started a trastuzumab containing treatment after biopsy.Conclusions: There was a substantial discordance in receptor status between primary tumor and liver metastases, which led to change in therapy for 21.8 % of patients. Biopsy of metastases for reassessment of biological features should be considered in all patients when safe and easy to perform, since it might impact treatment choice for many.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6003.
Pregnancy Related Breast Carcinoma: Comparison of Receptor Status with Age-Matched Controls.
Authors: Bhargava R. , Sukumvanich P. , Beriwal S. 
Published: December 2010

Abstract
Pregnancy related breast cancer (PRBC) is defined as breast cancer that is diagnosed during a pregnancy or within 1 year post-partum. These are generally considered as biologically aggressive tumors but the recent data suggests their prognosis to be similar to that of non-pregnant patients matched for age and stage. In the last few years, gene-expression profiling has been used to define breast cancer molecular classes with prognostic significance. The determination of tumor molecular class by immunohistochemistry is a reasonable alternative to molecular profiling. Therefore, we used immunohistochemical surrogate markers, estrogen receptors (ER), progesterone receptors (PR) and HER2 to determine breast cancer molecular classes in PRBC and compared them to age matched controls. ER and PR were scored using a semi-quantitative H-score like method that take into account both intensity and percentage cellular staining, and the score has a dynamic range of 0-300. An ER and PR score &gt;10 was considered a positive result. An ER/PR score of 200 or higher in a tumor was considered as strongly positive for the hormone receptor. HER2 was considered positive only if 3+ by IHC or unequivocally amplified by FISH. The tumors were classified as luminal A (LUMA), Luminal B (LUMB), Triple Negative (TN), ERBB2, Luminal A-HER2 Hybrid (LAHH), and Luminal B-HER2 Hybrid (LBHH). The immunohistochemical criteria, prevalence of molecular subtypes in PRBC and age matched controls (age less than 40 years) is shown in the table below. Statistical analysis was performed using SPSS software version 16.0. Chi-square test was performed to compare the differences in percentages between PRBC and the non-pregnant control group. A p-value &lt;0.05 was considered as significant.Tumor ClassCriteriaPregnancy related breast cancerAge matched controls (less than or equal to 40 years of age)LUMAStrong ER+; any PR; HER2 negative10/45 (22%)31/99 (31%)LUMBWeak to moderate ER+ or PR+; HER2 negative9/45 (20%)11/99 (11%)TNNegative for ER, PR and HER220/45 (25%)34/99 (34%)ERBB2Negative for ER and PR; HER2+4/45 (9%)3/99 (3%)LAHHStrong ER+; any PR; HER2+1/45 (2%)7/99 (8%)LBHHWeak to moderate ER+ or PR+; HER2 positive1/45 (2%)13/99 (13%) Comparison of tumor molecular classes using semi-quantitative ER, PR and HER2 results between PRBC and age matched controls shows no statistical difference between the 2 groups (p value of 0.06).The results suggest that PRBCs are not unique and rather represents aggressive biologic tumor types (i.e. triple negative tumors) that are characteristic for young age of the patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6012.
Histological Characterization of 47 Breast Cancers with Neoplastic Meningitis Evolution.
Authors: Le Rhun E. , Devos P. , Baranzelli M. , Faivre-Pierret M. , Bonneterre J. , Bonneterre J. 
Published: December 2010

Abstract
IntroductionAround 5% of patients with breast cancer develop neoplastic meningitis (NM). The prognosis of NM in this population is supposed to be better with a median survival time of 7 months if treated with intrathecal therapy, systemic treatment and adapted supportive care (versus 4-6 weeks if untreated). This evolution needs to be detected as early as possible and it is necessary to identify tumors with such a risk. We report histological characteristics in 47 breast cancers with leptomeningeal treated in our institution for the last 2 years.Aim of the studyTo identify histopathological characteristics of breast cancer predictive of leptomeningeal evolution.Patients and methods47 consecutive female breast cancer patients were diagnosed with neoplastic meningitis on the basis of cerebrospinal fluid (CSF) cytology and/or cerebrospinal MRI plus clinical symptoms. These patients were matched with 47 breast cancer's patients without leptomeningeal evolution, according to age at breast cancer diagnosis (+/- 2 years), year of breast cancer diagnosis (+/- 2 years) and use of systemic chemotherapy as initial treatment of breast cancer. Differences between the 2 groups of patients were analyzed using usual statistical methods (t-test, Chi square test).ResultsAt the time of NM diagnosis, the median (min-max) age of patients with NM was 51 (26-76) years. Median delay after breast cancer diagnosis was 33 months (0-193). Brain, hepatic, bone, lung metastases were present in respectively 47%, 43%, 47% and 19%. CSF cytology was positive in 72%, median proteinorachia was 0,75 g/l (0,17–16,12); cerebrospinal MRI was also positive in 87%. At the time of breast cancer, median age was 49 (25-70) years. Initial breast samples were tumor biopsy in 43%, partial mastectomy in 31% and total mastectomy in 27%. Breast tumors were invasive ductal carcinoma in 84% with histoprognostic grade II/III in 49/42%, MSBR grade I/II in 52/47%. Grade 3 of differentiation was observed in 68%, grade 3 of anisonucleosis in 59% and grade 1 of mitosis in 48%. In the tumors, estrogen/progesterone receptors (ER/PR) were detected in 67/48% and HER2 overexpression was observed in 24%. 19% of the tumors were triple negative. Vascular emboli were detected in 58% of the cases. Tumors were T2 in 43%, N+ in 66% and M+ in 14%. Significant differences between initial breast cancers with or without NM evolution concerned histological type (p = 0,043), ER (p = 0,004) and PR (p = 0,023), triple negative status (p = 0,009) and initial metastatic status (p &lt; 0,007).ConclusionsCarcinomatous meningitis preferentially occurs in invasive lobular tumors without hormonal receptors, particularly in triple negative tumors and in tumors metastatic upfront. HER2 overexpression is not a risk factor of NM, as is observed with brain metastases.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6013.
Automated Intra-Operative Analysis of Breast Cancer.
Authors: Martin D. , Ruidiaz M. , Ta C. , Sandoval S. , Cortes-Mateos M. , Messmer D. , Wang-Rodriguez J. , Kummel A. , Blair S. 
Published: December 2010

Abstract
Background: Multiple operations are a major problem for breast conservation therapy. Accurate interpretation of intra-operative tumor margins can limit multiple re-excision procedures in order to obtain negative margins while maintaining a good cosmetic result from BCT. Intra-operative touch preparations have been used in the past but can be difficult to interpret without an experienced cytopathologist.Objective: To examine the reliability of fluorescently labeled intra-operative touch preps in conjunction with automated analysis in correctly identifying cancer cells compared to final pathologic diagnosis.Methods: Touch preps were propctively performed on 38 consecutive cases of patients undergoing breast surgery. The surgical cases included 15 invasive tumors, 9 ductal carcinoma in situ, 5 prophylactic mastectomies, and 9 normal tissues from breast reduction operations. Tumors were grossly located by a surgical pathologist and a cross sectional cut was made at the suspected tumor center. Touch preps with poly-l-lysine coated slides were then taken on the tissue surfaces exposed from the cross sectional cut. Additionally, the location where the touch preps were performed was isolated in a cassette and separated for later comparison. In cases of benign disease, touch preps were performed at the center of the excised tissue. The slides were fixed in 95% ethanol and stained with a Cytokeratin, an epithelial cell marker, and Hoechst, a nuclear stain. The prepared slides were then imaged with an automated fluorescent microscope, and suspected cancer cells were detected through standard image processing and statistical techniques.Results: The overall accuracy of our automated fluorescence analysis was 95% for identifying invasive or pre-invasive cancer compared final pathologic diagnosis. The overall specificity was 100% (there were no false positives). The sensitivity for ductal carcinoma in situ was 75% and invasive cancer was 90%. Overall sensitivity was 87% which is comparable to the best reported results from manual examination of touch preparations.Conclusion: Automated analysis of fluorescently stained touch prep slides is highly accurate in identifying cancer with no false positives. The immunofluorescence stains and automated microscopy may help the pathologist to quickly identify cancer cells in fresh breast tissue during BCT operations, and, thus, limit breast re-excisions in the future.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6016.