bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel inflammatory breast cancer cell line, MDA-IBC-1 expresses and secretes WISP3, a putative tumor suppressor in inflammatory breast cancer.
Authors: Hall CS , Debeb BG , Xu W , Ueno NT , Reuben JM , Robertson F , Lucci A , Buchholz TA , Hortobagyi GN , Cristofanilli M , Woodward WA 
Published: December 2010

Abstract
Abstract #1051
Wnt-1-induced secreted protein 3 (WISP3) is a member of the CCN family of proteins, which also includes connective tissue growth factor (CTGF), Cy61, Nov, WISP1, and WISP2. WISP3, as well as the other CCN family members, plays important roles in cellular processes such as proliferation, migration, and survival. WISP3 was originally isolated as Lost in Inflammatory Breast Cancer (LIBC) based on its expression in only 20% of human IBC tumors. Lack of WISP3 expression has also been reported in the IBC-derived cell line SUM-149. In SUM149 cells WISP3 has been reported to function as a tumor suppressor capable of decreasing proliferation and maintaining an epithelial phenotype. Here we examine the expression of WISP3 in a novel aggressive IBC cell line with epithelial-mesenchymal transition (EMT) morphology and abundant WISP3 expression. MDA-IBC-1 cells were isolated from the pleural fluid of a patient with ER+, PR-, HER2/neu- IBC. In 2-dimensional (2D) adherent culture, MDA-IBC-1 cells exhibit fibroblast-like EMT morphology and express EMT-associated proteins such as N-cadherin, vimentin, and fibronectin. Correspondingly, E-cadherin protein expression is absent in 2D cultures. MDA-IBC-1 cells derived from 2D cultures form mammospheres when cultured in 3-dimensional (3D) progenitor promoting conditions. Interestingly, the expression of EMT molecular markers is absent in 3D progenitor promoting mammosphere culture. MDA-IBC-1 cells exhibit robust WISP3 protein expression in both 2D and 3D culture (1.8-fold higher in 3D). In addition, MDA-IBC-1 cells secrete WISP3 as indicated by the presence of WISP3 protein in MDA-IBC-1 derived conditioned media. WISP3 binding is reported to decrease insulin-like growth factor-1 (IGF-1) activation of the IGF1R signaling cascade in SUM-149 cells. IGFR1 protein is present in 2D and 3D cultured MDA-IBC-1 cells. IGF-1 protein overlay assays using conditioned media demonstrate a WISP3:IGF-1 interaction, suggesting functional folding. Serum-free MDA-IBC-1 conditioned media did not increase basal SUM149 proliferation and it inhibited IGF-1 stimulated proliferation to serum-free (basal) levels (p≤0.05). In addition, culturing SUM-149 cells in conditioned media obtained from IBC-1 cells significantly alters SUM-149 to a completely fibroblastic morphology. These data demonstrate that MDA-IBC-1 cells represent an IBC cell line with novel expression and regulation of WISP3. MDA-IBC-1 cells may better represent the cohort of IBC patients whose tumors express WISP3. This data suggest WISP3 may not function as a tumor suppressor in all IBC patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1051.
Immunohistochemistry-based marker profile accurately predicts risk in operable, hormone receptor-positive patients.
Authors: Linke SP , Bremer TM , Jacquemier J , Charafe-Jauffret E , Viens P , Birnbaum D 
Published: December 2010

Abstract
Abstract #1062
Background: The performance of current prognostic breast cancer tests is limited, because they only address simple additive molecular risks, and the results are often difficult to interpret in the context of overlapping clinicopathologic risks. Gene expression-based tests can be further confounded by contamination with non-tumor cells. Our goal was to develop a protein-based profile that addresses these limitations. Methods: ER, PR, Her2, EGFR, BCL2, p27/Kip1, and p53 (IHC) and MYC (FISH) were scored in tumor cells of FFPE tissue from patients with operable, pN0-2, hormone receptor-positive breast cancer at two clinical sites. A consensus prognostic model was trained using robust cross-validation in 290 hormone therapy (HT)-treated patients using statistical pattern recognition methods to account for complex marker interactions. Tumor grade, pT, and pN were directly incorporated into the model to the extent they were not replaced by the molecular markers. Continuous risk scores ranging from 0 to 10+ were generated for the 290 HT-treated patients, 90 untreated patients, and 119 patients treated with chemotherapy and HT. Results: A predetermined threshold of 3.8 separated HT-treated patients into high and low risk groups with hazard ratios of 8.8 (p&lt;1E-4) for metastasis and 13.0 (p&lt;1E-4) for disease-specific survival (DSS) without the need for an equivocal intermediate risk group. NPV/PPV were 96%/35% for metastasis at 10 yr and 97%/27% for DSS at 8 yr. In multivariate analyses, the profile was independent and fully replaced the significance of all individual prognostic factors and clinical treatment guideline combinations. Within treatment guideline elevated risk groups (Adjuvant! relapse risk &gt;15%, NPI &gt;3.4, and St. Gallen intermediate/high), the profile reclassified as low risk 84%, 81%, and 85% of pN0 patients, and 43%, 43%, and 32% of pN1 patients, respectively. The reclassified patients had &lt;10% 10-yr metastasis and &lt;5% 8-yr DSS event rates. In HT-treated patients with profile risk scores &gt;7.0, addition of chemotherapy produced a &gt;20% DSS benefit at 8 years (p=0.04). Conclusion: This 8-marker profile with super-additive algorithm achieved significantly higher classification accuracy than treatment guidelines and could aid selection of the most appropriate level of adjuvant therapy in patients with operable breast cancer.&#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1062.
Comparison of risk stratification by OncotypeDX versus HOXB13/IL17BR index and molecular grade index in 166 estrogen receptor positive patients from multiple institutions.
Authors: Sgroi D , Goss P , Steffel L , Lester S , Brock J , Hameed O , Hattab E , Ma X , Erlander M 
Published: December 2010

Abstract
Abstract #1072
Background&#x2028; We have previously reported two complementary prognostic markers in breast cancer for predicting risk of recurrence (Ma et al, Clin Cancer Res, 2008): a molecular grade index (MGI) that recapitulates grade 1 and 3 tumors and stratifies grade 2 tumors, and a gene expression index (HOXB13/IL17BR or H/I) that predicts clinical outcome in estrogen receptor positive (ER+) patients and endocrine benefit (Jerevell et al, Breast Cancer Res Treat, 2007). In combination, MGI and H/I define three risk groups: Low risk (low MGI), intermediate risk (low H/I, high MGI) and high risk (high H/I, high MGI). We conducted a study to compare risk stratification by MGI and H/I within samples for which a previous recurrence score (RS) by Oncotype Dx was reported.&#x2028; Materials and Methods&#x2028; RNA was extracted from formalin-fixed paraffin-embedded sections from all obtainable samples of patients (pts) from five institutions in which a RS was reported MGH, 77pts; Brigham, 48pts; IU, 19pts; UAB, 13pts; Scripps, 9pts. Real-time RT-PCR assays for MGI and H/I were completed and binary results of low and high for both were determined using pre-defined cutpoints. Risk stratification via MGI + H/I for each sample was compared to previously reported RS's (low, intermediate or high).&#x2028; Results&#x2028; For the 166 pts, 48% had a low, 45% intermediate and 7% high RS's. Overall, risk stratifications by RS versus MGI + H/I were significantly correlated (p &lt; 0.001) with 81% of patients with low RS also having low risk (low MGI). Risk stratification by H/I + MGI reduced intermediate risk via RS by 2.5-fold (45% versus 18%).&#x2028; &#x2028; Discussion&#x2028; In ER+ pts, MGI + H/I produces a significantly smaller group of patients with intermediate risk by re-stratifying a large number of patients with intermediate RS into low and high risk groups. Risk stratification by H/I + MGI in ER+ pts is by measurement of two discrete parameters: endocrine responsiveness (H/I) and proliferative status (MGI). This may allow for more informed treatment decisions by the treating oncologist. Further studies with clinical outcome are required to establish the clinical significance of these different risk stratification methods.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1072.
Is the prognostic value of Ki-67 dependent on ER status and histological grade?.
Authors: Klintman M , Bendahl P , Grabau D , Lövgren K , Malmström P , Fernö M 
Published: December 2010

Abstract
Abstract #1076
Purpose: Histological grade, tumor size, age, hormone receptor, and HER2 are established prognostic indicators for distant recurrences in node negative breast cancer. However, the role of the proliferation marker Ki-67 as a prognostic factor is still under debate. The aim of this study is to evaluate the additional prognostic value of Ki-67 in lymph node negative breast cancer.&#x2028; Patients and methods: In 200 consecutive premenopausal women with lymph node negative breast cancer, Ki-67 was determined using the monoclonal MIB-1 antibody on tissue microarray. High Ki-67 proliferation index was defined as &gt;20% positive tumor cells. Cox proportional hazards regression was used to model the impact of the prognostic factors on distant disease-free survival (DDFS). Due to non-proportional hazards, the analysis was restricted to the first 5 years after diagnosis, a time period during which 38 patients developed distant recurrences.&#x2028; Results: Strong positive correlations were observed between Ki-67, histological grade, S-phase, and HER-2. In univariate analysis, Ki-67 was a prognostic factor for DDFS (HR 2.9 95%CI: 1.5-5.7, p=0.002), as well as HER2, histological grade, age and ER. Tumor size was not a significant factor. In multivariate analysis, Ki-67 was an independent prognostic factor for DDFS (HR 2.3 95% CI: 1.0-5.0, p=0.044) together with HER2 and age, whereas tumor size and ER were not significant factors. Models including both Ki-67 and histological grade were not fitted due to colinearity. When stratifying for ER status Ki-67 was a significant prognostic factor in the ER positive group only (HR 5.1 95% CI: 2.0-13, p=0.001, univariate analysis) and significant interaction between the two markers was found (p=0.02). When stratifying for histological grade, Ki-67 could divide the patients with histological grade 2 (n=69; 10 distant recurrences) into two separate groups with significant difference in DDFS (HR 15 95% CI: 3.7-57, p=0.0001). This remained significant after adjustment for age and HER2 status. In histological grade 1 and 3, Ki-67 provided no additional prognostic information.&#x2028; Conclusion: This study demonstrates that Ki-67 is an independent prognostic factor for premenopausal patients with lymph node negative breast cancer. It is noteworthy that Ki-67 adds prognostic information in ER positive patients, but not in ER negative, and in patients with histological grade 2, but not in patients with histological grade 1 and 3. Taken together, Ki-67 may be clinically helpful for prognostic considerations and for selection of adjuvant treatment.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1076.
Expression of fatty acid synthase as a prognostic marker in triple negative breast cancer.
Authors: Kang S , Jeon Y , Lee S , Bae Y 
Published: December 2010

Abstract
Abstract #1082
Background: Fatty acid synthase (FAS), the key enzyme required for fatty acid biosynthesis, is minimally expressed in most normal human tissue. Recent studies have demonstrated that hyperactivity or overexpression of FAS is a common feature in subset of sex steroid-related tumors, including breast carcinoma. Moreover, up-regulation of FAS gene expression is more pronounced in more advanced tumors, and strong expression of FAS seems to be associated with a poor prognosis of breast cancer. We examined the expression of FAS in invasive breast carcinomas to investigate the prognostic value of FAS expression in a large cohort of breast carcinomas with long term follow up data.&#x2028; Methods: Five hundred and ninety six cases of invasive breast carcinoma, retrospectively selected from 1987-2004, were incorporated into tissue microarrays (TMAs). We performed immunohistochemical stains for FAS, ER, progesterone receptor (PR) and Her-2/neu. Triple-negative breast cancers (TNBCs) were defined as those with ER-, PR- and Her-2/neu-negative results. The results of immunohistochemical stains were correlated with other known clinicopathologic parameters and evaluated for an effect on estimating prognosis.&#x2028; Results: The mean age at diagnosis was 47.2 (ranges 20∼85 years) with a mean tumor size of 2.5cm (ranges 0.4∼11cm). The expression of FAS was positive in 437 (73.3%) cases. There was no significant correlation between the expression of FAS and clinicopathologic characteristics of the tumor (age, tumor size, lymph node metastasis and lymphovascular invasion) (p&gt;0.05). FAS expression was inversely correlated with histologic grade (p=0.009) and positively correlated with the expression of ER (p&lt;0.001), PR (p&lt;0.001) and Her-2/neu (p&lt;0.001). One hundred thirty eight of 596 cases (23.1%) were TNBCs. FAS-expressing breast invasive carcinomas had a higher tendency to have triple-negative phenotype when compared to FAS-negative cancers (p&lt;0.001) with a mean follow up of 72.3 months, there was no significant survival difference according to the FAS expression (p&gt;0.05). However, FAS-positive group showed shorter disease free survival (DFS) (p=0.014) and overall survival (OS) (p=0.021) than FAS-negative group in patients with TNBC.&#x2028; Conclusion: This study showed that FAS expression is strongly associated with the expression of hormonal receptors and Her-2/neu in invasive breast carcinomas. Especially FAS could be a potential prognostic marker in TNBCs.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1082.
The importance of updating the family history of breast cancer survivors.
Authors: Madlensky L , Wasserman L , Parker BA , Pierce JP 
Published: December 2010

Abstract
Abstract #1097
BACKGROUND: The cancer family history is the most important tool in identifying women who may be at high risk of having the hereditary breast-ovarian cancer syndrome (HBOCS) caused by mutations in the BRCA1 and BRCA2 genes. While many breast cancer patients may be asked about their family history at the time of their initial diagnosis, it is not known how many women initially classified as low risk of HBOCS become high risk of HBOCS over time, as new cancers are diagnosed in their relatives.&#x2028; PURPOSE: 1)To determine how the prevalence of "high risk" cancer family histories changes over time in cancer patients, and; 2) To determine how many breast cancer survivors at high risk for HBOCS self-report having had genetic testing for BRCA1/2.&#x2028; METHODS: Breast cancer survivors in the Women's Healthy Eating and Living (WHEL) study provided detailed family history data at baseline and again at study closure. The Myriad prevalence tables were used to categorize survivors as "high risk" of HBOCS if their risk of having a mutation in BRCA1/2 was 10% or greater.&#x2028; RESULTS: At baseline, 8.2% of 2508 survivors were classified as high risk. At follow-up (avg. 7.5 years later), an additional 5.8% of women became high risk due to new cancers in their families. Among high-risk survivors, 15% reported that they had never heard of BRCA testing. Of the 85% who had heard of testing, 23% reported that they had been tested.&#x2028; CONCLUSIONS: The prevalence of "high risk" cancer family histories increased by 70% in a cohort of breast cancer survivors over 7.5 years. It is important for clinicians to identify high-risk families not only at initial diagnosis, but to update the family history periodically. A substantial proportion of high-risk women had never heard of BRCA1/2 testing, and could benefit from genetic counseling to discuss the cancer risk in their families.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1097.
BRCA1 c.5181_5183delGTT (p.Val1688del) is a true pathogenic mutation that affects both protein stability and function: implications for genetic counseling.
Authors: De Nicolo A , Pathania S , Parisini E , Branda KJ , Stoeckert K , Garber JE 
Published: December 2010

Abstract
Abstract #1106
Germ line mutations in the BRCA1 tumor suppressor gene are associated with a significantly increased lifetime risk of breast and/or ovarian cancers. Since genetic testing has become a routinely step in the clinical practice, the discrimination between pathogenic mutations and benign variants appears a mandatory task as it can facilitate risk estimation and surveillance, as well as implementation of cancer prevention and treatment strategies. Most of the deleterious BRCA1 mutations identified so far are frameshift or nonsense ones that result in a premature translational truncation of the protein; only a small percentage is represented by missense mutations residing in the N-terminal RING finger or in the C-terminal BRCT domains. Interestingly, a growing number of variants of unknown significance (VUSs) are being described, which lack ad hoc functional assays thus remaining unclassified with respect to their pathogenic or neutral effect.&#x2028; Recently, disease-causality was predicted, based upon a multifactorial likelihood approach, for a BRCA1 VUS, c.5181_5183delGTT (p.Val1688del), recurrent in Italian breast/ovarian cancer families (Malacrida et al., 2008). The same VUS was also identified in one of the families recruited at the Dana-Farber Cancer Institute: pedigree analysis revealed early onset breast cancer in both the proband and her mother; family history confirmed Italian descent.&#x2028; To gain insights into the specific risk associated with the BRCA1 c.5181_5183delGTT (p.Val1688del) VUS, we investigated its impact on BRCA1 function. The sequence variant causes a single amino acid in frame deletion that falls within the first of the two tandem BRCA1 BRCTs. A series of approaches, including protein stability assays and co-immunoprecipitation experiments, as well as structural modeling based on sequence alignment, were employed to characterize both the full-length mutant protein (ΔValBRCA1) and its C-terminal fragment.&#x2028; We observed that ΔValBRCA1 displayed decreased stability when compared to the wild type counterpart. Moreover, when tested, interactions with known BRCA1 partners, BRIP1 and CtIP, were completely abrogated. In addition, ΔValBRCA1 failed to interact with Rap80 and was deficient in DNA damage response and repair by homologous recombination. These results demonstrate that BRCA1 c.5181_5183delGTT (p.Val1688del) is a true pathogenic sequence alteration and provide the first evidence of its effect on the stability and function of the encoded protein. We believe that our findings will impact the genetic counseling of those patients who harbor this newly defined mutation and their family members thus allowing them to benefit of appropriate risk assessment, prevention and therapeutic strategies.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1106.
Decreased TGFβ signaling and increased COX2 expression in high risk women with increased mammographic breast density.
Authors: Yang WT , Lewis MT , Wong H , Hess K , Tsimelzon A , Karadag N , Cairo M , Meric-Bernstam F , Sahin A , Chang JC 
Published: December 2010

Abstract
Abstract #1107
Background&#x2028; High mammographic density is associated with up to a 6-fold increased risk of breast cancer. Pathways responsible for this increased density are unknown. We hypothesize that specific molecular pathways exist that are associated with increased mammographic density and breast cancer risk, and may therefore be used to identify potential targets for chemoprevention.&#x2028; Methods&#x2028; Histologically confirmed normal breast tissue was collected from women undergoing breast surgery who had available demographic data and mammograms for review. Breast parenchymal density was classified according to the American College of Radiology's Breast Imaging – Reporting and Data System reporting system. Quantitative classification of mammographic parenchyma was performed using thresholding method and percent density. Women with low (less than 50%) versus high (greater than 50%) breast density were compared. Double-stranded cDNA was synthesized from the normal breast tissue using an oligo-dT primer containing a T7 RNA polymerase promoter, followed by in vitro transcription with biotinylated ribonucleotides. The labeled cRNA was hybridized to Affymetrix HG U133Plus2 chips which comprise ∼28,600 genes to determine gene expression patterns. Immunohistochemical analysis (IHC) of estrogen receptor, progesterone receptor, proliferation (Ki67) and COX2 expression was performed.&#x2028; Results&#x2028; Sixty-two women were identified, 26 (42%) had high, and 36 (58%) had low mammographic density. Neither age, menopausal nor hormone receptor status influenced the gene expression pattern. Seventy-three genes had differential expression between normal breast tissue with high and low mammographic density (p&lt;0.001, fold change&gt;1.5) and had a low false discovery rate (&lt;10%). Of these 73 differentially expressed genes, network and canonical pathway analysis demonstrate decreased TGFβ signaling (TGFBR2, SOS, SMAD3 and CD44 expression) in dense breast relative to non-dense breast. By IHC, Ki67 (stroma) and COX2 expression were significantly higher in dense breasts (p&lt;0.05) on univariate analysis, and only COX2 expression in the stroma was statistically significant at (p&lt;0.01) on multivariate analysis.&#x2028; Conclusion&#x2028; TGFβ ligands are currently the only growth factors known to prevent mammary epithelial cell proliferation. TGFβ has been reported to influence COX-2 expression, and these molecules are highly differentially expressed in individuals at high risk of developing breast cancer. These results suggest that COX2 inhibition should be further investigated for breast cancer prevention despite possible increase in cardiovascular risk.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1107.