bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cisplatinum Sensitivity of BRCA1-Mutated HCC1937 Breast Cancer Cells Is Linked to Impairment of Notch Signaling and Is Increased by γ-Secretase Inhibitors.
Authors: Ventura M. , Di Martino M. , Arbitrio M. , Propato M. , Perri G. , Bulotta A. , Calimeri T. , Pacicca M. , Tassone P. , Tagliaferri P. 
Published: December 2010

Abstract
BRCA1 plays a critical role in DNA-damage repair mechanisms elicited by cell exposure to anti-tumor agents. HCC1937 is a BRCA1-defective breast cancer cell line which discloses higher sensitivity to cisplatinum (CDDP) as compared to the BRCA1 full-length cDNA transfected clone, HCC1937/wtBRCA1. By cDNA microarray whole gene expression profile and Ingenuity Pathway Analysis (IPA) software, we found a differential modulation of Notch signaling after CDDP exposure in HCC1937 cell line as compared to BRCA1-reconstituted clone with a strong down-regulation of Notch1, 2 and 3 expression together with other genes involved in the Notch signaling network, including Hes1 and Jag1. Notch pathway was not affected by CDDP exposure in BRCA1-reconstituted cells. By Western Blot analysis, we next analyzed if the different trascriptional response of the two cell lines to CDDP occurred together with down-regulation of Notch protein in BRCA1-defective cells. We found enhanced expression of BRCA1 in BRCA1-transfected cells. We then analyzed the Notch 3 protein's expression in HCC1937 and HCC1937/wtBRCA1. By Western blot analysis, we demonstrated a significant reduction of Notch 3 protein's expression following CDDP exposure at the IC50 dose for 12, 18 and 24 hours, in HCC1937 as compared to HCC1937/wtBRCA1, consistently with gene expression results. In the aim of evaluating the role of Notch signaling in the regulation of the pharmacological response to CDDP in BRCA1-defective cells, we exposed HCC1937 cells to the pan-Notch inhibitor, γ-secretase inhibitor XII (GSI-XII), alone or in combination with CDDP, and we elvaluated, by MTT assay, in vitro growth effects on cell survival. We observed a time and dose dependent decrease of cell growth of HCC1937 following GSI-XII exposure as compared to BRCA1-reconstituted clone, with an IC50 between 25 and 35 microM as single agent, while HCC1937/wtBRCA1 where highly resistant to the drug. The combination of GSI-XII plus CDDP produced a significant sinergistic antitumor effect at 48 hours in HCC1937 which did not occurred in HCC1937/wtBRCA1. Our findings suggest that the high sensitivity of BRCA1-defective cells to CDDP exposure may be related not only to depression of the DNA-damage repair machinery but also to down-modulation of the Notch survival pathway. Moreover, our data indicate that the antitumor activity of CDDP is enhanced by combination with the Notch inhibitor GSI-XII suggesting that γ-secretase inhibitors may represent a potential and novel therapeutic tool in this specific setting.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3128.
Examining the Role of ErbB2 in a Mouse Model of Type I Insulin like Growth Factor Receptor-Induced Mammary Tumourigenesis.
Authors: Campbell C. , Moorehead R. 
Published: December 2010

Abstract
Background: The type I insulin-like growth factor receptor (IGF-IR) and epidermal growth factor receptor 2 (ErbB2) are both receptor tyrosine kinases extensively implicated in human breast cancer. The IGF-IR is involved in cell proliferation and survival and is overexpressed in a large proportion of breast cancers. Similarly, ErbB2 (Her2) has been identified as a key contributor to a relatively large subset of aggressive breast cancer and is currently the basis for clinical therapeutics. To examine how the IGF-IR contributes to breast cancer and to study this receptor as a potential therapeutic target, we have previously created an inducible transgenic mouse model of IGF-IR overexpression in the mammary gland. In this model, tumours rapidly form upon induction of the transgene, with metastasis to the lung occurring in approximately 25% of animals. In addition, the RM11A cell line was isolated from tumour tissue and was shown to maintain inducible IGF-IR overexpression. The purpose of this study was to examine the interaction between IGF-IR and ErbB2 using our model.Materials and Methods: Protein expression was studied through Western blotting. ErbB2 expression was manipulated through the use of siRNA (for downregulation) and through the use of a plasmid encoding ErbB2 (for upregulation). Stable overexpression of ErbB2 was achieved through transfection of this plasmid with subsequent selection of stable integrants. Tumourigenicity was assessed by direct injection of these cells into the mammary gland. MTT assays and Ki67 staining (through immunofluoresence or immunohistochemistry) were used to examine cell survival and proliferation.Reults: In RM11A cells, survival was impaired upon downregulation and inhibition of ErbB2 in vitro. In our transgenic mouse model, ErbB2 was upregulated in primary tumours overexpressing the IGF-IR and was downregulated upon removal of IGF-IR induction and also in IGF-IR-independent recurrent tumours. In vivo, overexpression of ErbB2 conferred a more aggressive phenotype to RM11A cells. However, ErbB2 overexpression did not enhance proliferation in these cells in vitro or in vivo. The mechanism through which ErbB2 enhances tumourigenesis in or model is currently being investigated.Discussion: ErbB2 appears to have a role in IGF-IR-induced mammary tumourigenesis and can enhance tumour growth. Also, the IGF-IR appears to function in the regulation of ErbB2 in our model. Understanding how these two potent oncogenes interact to promote mammary tumourigenesis will ultimately help in designing treatment regimes specifically targeting the IGF-IR and/or ErbB2.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3156.
Identification of Interferon Regulatory Factor (IRF)-5 Tumor Suppressor Function in Human Breast Cancer.
Authors: Bi X. , Barnes B. 
Published: December 2010

Abstract
Background: Transcription factors of the IRF family participate in the early host response to pathogens, hematopoietic differentiation and immunomodulation. IRFs can regulate cell growth and apoptosis thereby affecting the susceptibility to and progression of cancer. IRF-1 was recently identified as a tumor suppressor in breast cancer. Early evidence from our lab and others suggests that IRF-5 may also have tumor suppressor activities. Although loss of IRF-5 expression has recently been shown to enhance transformation by Ha-ras, very little is known of IRF-5 tumor suppressor function(s).Material and Methods: Using paraffin-embedded formalin-fixed human breast tissue specimens from 64 patients with varying stages of ductal carcinoma, we analyzed and compared the expression of IRF-1 and IRF-5 by immunofluorescence (IF). Clinical data, such as histological subtype, stage, and receptor expression (ER, PR Her-2) were available for clinicopathological correlations. Protein levels were also determined in normal human breast epithelial MCF-10A, and -12A cells, and in cancer cell lines MCF-7, MDA-MB-231, -468, and T47D by immunoblot and IF. By retroviral infection, we overexpressed IRF-5 in breast cancer cell lines or knocked-down IRF-5 in normal MCF-10A and -12A cells and examined cell growth, apoptosis, metastasis and sensitivity to cytotoxic stress. In vivo tumor suppressor function was determined in NCr nu/nu mice inoculated with MCF-7 or MDA-MB-231 cells expressing or lacking IRF-5.Results: We confirmed recent data on IRF-1 revealing that it is expressed less frequently in tumor tissue of high-grade ductal carcinoma in situ (DCIS) or invasive DC compared with normal breast tissue. Data from patient samples indicate a significant difference between IRF-1 and IRF-5 expression that was distinctly associated with breast cancer disease stages, including early-to-late stage DCIS, suggesting their utilization as prognostic indicators.Similar findings were made in breast cancer cell lines. We demonstrate that forced expression of IRF-5 in breast cancer cells inhibits colony formation, sensitizes cells to cytotoxic stress-induced apoptosis, inhibits metastasis, and tumor formation in nude mice. Conversely, knockdown of IRF-5 in MCF-10A and -12A cells resulted in resistance to stress-induced cell death.Discussion: Data from this study strongly support a tumor suppressor function for IRF-5 in breast cancer. Ultimately, the study is expected to lead us to the identification of new prognostic indicators and therapeutic approaches for the treatment of breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3160.
p53 Mutation in Inflammatory Breast Cancer Cell Lines.
Authors: Li C. , Lee B. , Woodward W. , Ueno N. , Robertson F. , Reuben J. , Cristofanilli M. 
Published: December 2010

Abstract
Background: Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary breast cancer and represents 1% to 2% of primary breast cancer in the United States. IBC is characterized by an acute inflammation of the skin of the affected breast generally believed to be caused by blockage of the dermal lymphatics by tumor emboli. Wild type (WT) p53 is a tumor suppressor gene, which induces apoptosis and p53 mutations are associated with poor prognosis in breast cancer. Compared with locally advanced breast cancers, IBC patients have higher levels of mutated p53 protein that has been associated with more aggressive tumors, anthracycline resistance, shorter progression free survival, shorter overall survival, and less favorable long-term outcome. The aim of this study was to determine if there are unique genetic variations in IBC cell lines that would provide specific genetic p53 mutations that could be exploited for targeted therapy with the intent of improving response to treatment and overall survival in IBC.Materials and Methods: Genomic DNA was extracted from six breast cancer cell lines (MDA-453, SUM149, MCF-7, KPL4, MDA321, and SUM190) and the immortalized human mammary epithelial cells (HMLE) using the Qiagen DNA Blood Mini Kit (Valencia, CA). Among the 6 breast cancer cell lines, KPL-4, SUM149 and SUM190 are IBC cell lines; MDA231 and SUM149 have basal-like phenotype; MCF-7 has wild-type p53; SUM190 and KPL-4 are Her2 amplified. The DNA purity and concentration were determined by spectrophotometric measurements of absorbance at 260nm and 280 nm. Polymerase chainreaction (PCR) was performed to amplify the fragments of exons 2-11 of the p53gene using consensus primers. The PCR products were scanned and identified using the Agilent Bioanalyzer 2100. DNA sequencing was performed on PCR products in the ABI PRISM 310 Genetic Analyzer. The BLAST search was used to identify p53 mutations compared with the reference sequence, X54156, from Genbank.Results: We screened 2-11 exon sequences of the p53 gene in the 7 human breast cell lines. We identified two IBC cell lines (SUM149, SUM-190) with a p53 gene alteration that predicted a change in the encoded protein, SUM149 at exon 7 (ATG to ATA, Met-237-Ile) and SUM190 at exon 9 (CAG to TAG, Gln -317-stop). Both mutations have been previously reported. Five nonsense mutations were identified in two other cell lines, MDA-453 and MDA321. No mutations were identified in KPL4 and HMLE cells.Conclusions: The p53 mutation profile in breast cancer cell lines suggests an additional biological feature for the characterization of IBC. Furthermore, these data support the previously reported association between p53 status and chemo- and radioresistance in this disease responsible for poor prognosis. Therapies directed to restore p53 function should be explored in IBC models and in clinical trials.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3161.
Mitotic Activity Index Identifies Both Over- and Undertreated Lymph Node Negative Breast Cancer Patients &lt; 55 Year According to the Norwegian Treatment Guidelines.
Authors: Hoel Lende T. , Hoel Lende T. , Hoel Lende T. , Gudlaugsson E. , Gudlaugsson E. , Janssen E. , Voorhorst F. , Van Diest P. , Søiland H. , Baak J. , Baak J. , Baak J. 
Published: December 2010

Abstract
Background: It is a challenge to avoid under- and overtreatment of breast cancer patients in the adjuvant setting. Patients who have not received adjuvant systemic treatment and with a known outcome demonstrate the natural course of the disease after surgery. Such patients may be re-evaluated in specific guidelines like the Norwegian Breast Cancer Group (NBCG) based on the St. Gallen criteria. NBCG classify the patients in a low-risk group which should not receive systemic treatment, and a high-risk group which should be offered such therapy. New factors may be evaluated in these two strata, possibly discriminating groups of under- or overtreated patients. The aim of this study was to explore if the previous established marker of proliferation, the mitotic activity index (MAI), could give any additional information.Patients and methods: The study comprised 516 lymph node negative patients &lt; 55 years from the Dutch prospective Multicenter Morphometric Mammary Carcinoma Project (MMMCP; 1987-1989)1. No adjuvant systemic treatment was given after surgery to these patients. The guidelines from NBCG-2005 were used to classify the patients in “NBCG low-risk” group (n=100) defined as pT1/Grade 1, all ages and pT1a-b/Grade 2-3, &gt;35 years, all hormone receptor positive. The rest of the patients (n=416) was grouped as “NBCG high-risk”. Breast Cancer Specific Survival (BCSS) was estimated by the Kaplan-Meier method. MAI was analyzed after a standardized protocol in the invasive front of the tumor. The previous established thresholds of MAI with low (&lt;3), intermediate (3-9) and high (≥10) proliferation were used in the calculations.Results: In the “NBCG low-risk” group 10 % of the patients had MAI ≥10. These had a 14-years BCSS of 50 % (HR=15.47, 95 % CI=3.61-66.30) and may be regarded as undertreated patients. Patients with MAI &lt;3 and 3-9 had a BCSS of 95 % and 83 % respectively. In the “NBCG high-risk”group 24 % of the patients with MAI&lt;3 had a 14-years BCSS of 92 % indicating overtreatment. Furthermore, patients with MAI 3-9 and ≥10 had a BCSS of 74 % and 63 % (p-trend &lt;0.0001).Discussion: MAI represents the “converging mitotic drive” from all cellular signal pathways in the peripheral growing zone of the tumor, where also micro-environmental factors are known to influence proliferation of cancer cells. This may explain why MAI gives original information strong enough to identify subgroups breast cancer patients who would not get optimal adjuvant treatment. A disadvantage of this study is that the HER-2 status in this MMMCP material is not known. National prospective studies are needed to verify our results.1 Baak, JPA et al: Pathol Res Pract 185:664-70,1989.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3182.
Reduced Lung Cancer Mortality Risk among Breast Cancer Patients Treated with Anti-Estrogens.
Authors: Rapiti E. , Verkooijen H. , Verkooijen H. , Fioretta G. , Schubert H. , Vinh-Hung V. , Vinh-Hung V. , Benhamou S. , Vlastos G. , Bouchardy C. 
Published: December 2010

Abstract
Background: The Women Health Initiative study recently reported that women on hormone replacement therapy (HRT) were at increased risk of dying from lung cancer. If exposure to estrogens can worsen lung cancer outcome, we hypothesized that anti-estrogens may, on the contrary, improve its prognosis. We compared lung cancer incidence and mortality among breast cancer patients with and without anti-estrogen therapy.Methods: All 6715 patients recorded with a breast cancer in the population-based Geneva Cancer registry in the period 1980-2003 were included in the study. Forty-six percent of these women (3066) received anti-estrogen therapy (tamoxifen in large majority). Age, sex and year-specific population data were used to calculate standardised incidence ratios (SIRs) and standardised mortality ratios (SMRs), to compare the study population to the general female population of Geneva canton. For each woman we computed person-years at risk from the date of diagnosis of breast cancer to the date of diagnosis of invasive lung cancer cancer, date of death, date lost to follow-up, or end of the study period (December 31, 2007).Results: The cohort yielded a total of 57,100 person-years.During the study period we observed a total of 40 cases of metachronous lung cancers (diagnosed at least six months after the breast cancer). Compared with the general population, the risk of developing a lung cancer among women who received anti-estrogens was 0.63 (95% Confidence Intervals [CI]: 0.33-1.10) and among women without anti-estrogens was 1.12 (95% CI: 0.74-1.62). Lung cancer mortality rate was 31.44/100,000. The mortality rate were 9.23/100,000 for women with anti-estrogens and 44.97/100,000 for women without anti-estrogens.Compared to the general population the SMR for lung cancer was 0.13 (95% CI: 0.02-0.47) among women who took anti-estrogens (p&lt;0.001), and 0.76 (95% CI: 0.43-1.23) among women who did not receive anti-estrogens.Discussion: Women who received anti-estrogens as breast cancer treatment have a significantly decreased risk of dying from lung cancer. This result further supports the role of estrogens in lung cancer prognosis and suggests that exposure to anti-estrogens may offer some protection against tumor mortality.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 35.
Using Ki67 To Improve and Simplify Outcome Modeling for Breast Cancer.
Authors: Yerushalmi R. , Woods R. , Ravdin P. , Speers C. , Kennecke H. , Gelmon K. 
Published: December 2010

Abstract
Ki67 is a marker of proliferation which has several advantages over histological grade. Ki67 is determined less subjectively and is a continuous rather than a categorical variable. Many studies that have looked at Ki67 have been small and underpowered. A large population based tissue microarray was used to: A) test the prognostic value of Ki67 in testing and validation sets, and B) construct an improved model including Ki67 and conventional prognostic variables to predict patient outcome. Methods: The cohort included 2,780 patients with early breast cancer diagnosed in British Columbia and a median follow up of 14.5yrs. Variables included were: tumor size (T), number of positive nodes (N), grade, lymphovascular invasion (LVI), estrogen receptors (ER), progesterone receptors (PR), Her2, Ki67, local treatment (surgery, radiation) and systemic treatment (chemotherapy, hormonal). Prognostic factors were balanced between the training and validation sets. Prognostic variables were identified in the testing set among ER positive and ER negative cohorts using Cox Regression analysis and tested in the validation set. Results: The inclusion of Ki67 in the Cox Regression analysis resulted in the elimination of grade as a predictor. For ER positive disease independent predictors were T, N, LVI, PR, HER2, Ki67, local treatment, chemotherapy and hormonal therapy. Independent predictors among ER- cases were T, N, LVI, Ki-67, and chemotherapy. Predicted 10-yr Breast Cancer Specific Survival in the validation set was 72.0% versus 72.4% [SE: 1.2] observed. As subtle prognostic differences may result in very disparate treatment recommendations for Stage I breast cancers, we specifically reviewed this group. In analysis of stage I patients, there were no statistically significant deviations between predictions and observation; agreement between the predicted and observed 10-yr BCSS was excellent (86.0% vs 87.6% (SE: 1.6) p = 0.3169). As well, elevated Ki67 was common (53%) and was a powerful prognostic variable with causing more than a doubling of the 10-yr BrCa mortality (elevated ≥ 10% vs low &lt; 10%, 16.8% vs 6.8%) in this group (table). Conclusion: In this study the proliferation marker Ki67 replaced histologic grade as a predictor of outcome for patients with early breast cancer. Predictive models such as Adjuvant! could incorporate Ki67 as an input variable and this modification is being developed. If models that use Ki67 are validated they may be able to be used globally and be cost effective compared to more expensive genomic predictors.Table: Predicted versus observed 10yr BCSS, based on the new modelPatientsSubgroupNPredicted SurvivalObserved Survivalp-valueAll patientsOverall139772.072.40.75 ER+101277.276.40.56 ER-38558.461.20.27 HER2+19755.658.00.50 HER2-120074.874.80.99Stage IOverall45386.087.60.32 ER+35287.690.40.09 ER-10179.678.40.77 HER2+4378.882.40.55 HER2-41086.888.40.33
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4042.
Triple Negative Breast Cancer Has a Worse Prognosis within 3 Years after Treatment Compared to Non-Triple Negative Breast Cancer.
Authors: Lee Y. , Kwon S. , Ko B. , Seo J. , Lee J. , Kim H. , Lim W. , Ahn S. , Son B. 
Published: December 2010

Abstract
BackgroundTriple negative breast cancers (TNBC) become known as poor prognosis generally. Our purpose was to compare the clinical features and outcomes for TNBC with other subtypes of breast cancers in Korea.MethodsWe included 2,907 patients who diagnosed breast cancer and treated at Asan Medical Center from 2003 to 2005. Clinical and pathologic parameters, disease-free survival (DFS) and overall survival (OS) were compared between patients with TNBC and non-TNBC. All features were reviewed throughout medical records retrospectively.Results622 patients (21.4%) had TNBC. TNBC patients was associated with younger age, larger size, positive nodal involvement, overweight, family history, elevation of CaAg15-3, high tumor grade, positive p53 compared non-TNBC. The patients were followed for a median of 54 months (range 1-76 months). Relapse-free survival was 86.3% and 92.6% for TNBC and non-TNBC, respectively, with significant difference (P&lt;0.0001). Overall survival was also 88.9% and 96.1% for TNBC and non-TNBC (P&lt;0.0001). Compared with non-TNBC patients, TNBC had an increased likelihood of recurrence and death within 3 years after diagnosis but not thereafter. In non-TNBC, the recurrence risk and death risk seemed to be relatively constant. In univariate analysis for worse prognostic factors of TNBC associated with DFS and OS revealed that statistically significant in large tumor size, nodal status, CA15-3, Lymphovascular invasion. In multivariate analysis, nodal status was a prognostic factor for DFS (P=0.06, HR=2.28; 95% CI, 0.92-3.04) and OS (P&lt;0.0001, HR=5.22; 95% CI, 2.11-12.96) of TNBC. Lymphovascular invasion was only poor prognostic factor for DFS (P=0.026, HR=10.2, 95% CI, 1.31-76.8), not for OS.ConclusionsTNBC has a worse prognosis than non-TNBC patients, but this effect is limited within 3 years after diagnosis. The most competent prognostic factor of recurrence and death for TNBC is a nodal status. We plan that perform analysis for prognosis according to hormone receptor and HER-2 receptor status sooner.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4044.