bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-02-03: TGF-b1-inducible protein BIGH3 (transforming growth factor beta-induced gene human clone 3): A new mechanism inducing breast cancer cell apoptosis
Authors: RezaPoor F , Moritz R , Phelix CF , LeBaron RG 
Published: August 2014

Abstract
Cancer development and progression is a complex process involving tumor cell mechanisms as well as tumor-host cell interactions. Using autocrine and paracrine mechanisms the cytokine TGF-b1 can influence cancer progression, in part through promoting the synthesis and secretion of extracellular matrix molecules. TGF-β1 strongly upregulates the gene TGFBI, which encodes a secretory protein named BIGH3. BIGH3 is an extracellular matrix, adhesion-class proapoptotic protein characterized by four fasciclin-1 (FAS1)-like domains, a cysteine-rich region and several different integrin-binding sequences. The C-terminus of BIGH3 encodes the integrin-binding peptides EPDIM and RGD. These sequences, and the integrin α3β1, have been implicated as important components of BIGH3-induced apoptosis. Breast cancer cells express the integrin α3β1, which is reported to play various roles including signaling, invasion and metastasis. Breast cancer cells and tumor-host cells express BIGH3 protein, which is expected to accumulate in the presence of TGF-β1. The above findings highlight the molecules TGF-β1 and α3β1 in tumor progression and are the basis for our hypothesis that BIGH3 protein itself is sufficient to induce an increase in breast cancer cell apoptosis. In order to test this hypothesis we utilized human breast cancer MCF-7 cells, human recombinant BIGH3 and TUNEL assays. Here, we show for the first time that exogenous human recombinant BIGH3 in cancer cell growth medium evokes a statistically significant increase in breast cancer cell apoptosis. A concentration curve shows that there is a direct relationship between the quantity of BIGH3 in the cells’ milieu and the number of cells undergoing apoptosis. This finding is consistent with receptor-ligand binding and indicates that BIGH3 is a potential target for breast cancer treatment. Importantly, in-house developed anti-BIGH3 antibody completely blocked apoptosis when compared to apoptotic cells in negative control conditions. Stimulation of BIGH3 gene expression in breast cancer cells, and providing exogenous BIGH3 to breast cancer cells, are expected to diminish breast cancer progression. Along this line, BIGH3 may be valuable as an agent for neoadjuvant or adjuvant therapy for human breast cancer patients.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-02-03.
Abstract P6-04-17: The irreversible c-Jun N-terminal kinase (JNK) inhibitor, JNK-IN-8, sensitizes basal-like breast cancer cells to lapatinib
Authors: Ebelt ND , Van Den Berg CL 
Published: August 2014

Abstract
Basal-like breast cancers represent 15-20% of breast cancers diagnosed each year. These tumors appear earlier in life and have the worst prognosis due to high prevalence of metastasis. Endocrine and molecularly targeted therapies such as trastuzumab or lapatinib are ineffective against this tumor subtype. A high frequency of p53 mutations, low BRCA1 expression along with high epidermal growth factor receptor (EGFR) expression provide some insight into what types of targeted therapies may be useful for basal-like tumors in the future. We have recently shown that JNK2 mediates the expression of p53 and BRCA1 in response to EGFR activation to promote epithelial to mesenchymal transition and metastasis. Further, high JNK2 expression is associated with poorer survival in patients with basal-like breast cancer. These findings suggest that the JNK pathway may be a promising target for basal-type breast cancer treatment.
Commonly used competitive ATP inhibitors of JNK have suffered from lack of specificity for JNK. However, the Gray laboratory recently developed highly specific covalent inhibitors of JNK (Zhang, et al. 2012). The agent showing the best properties is JNK-IN-8. Our data show that treatment of human and mouse basal-like, breast cancer cell lines with JNK-IN-8 sensitizes them to lapatinib. Single agents had minor affects on cell viability and cell cycle regulation, but combination treatment led to G2/M arrest and endoreduplication along with synergistic apoptotic responses. Further, the expression and electrophoretic mobility of mitotic arrest deficient 2 (MAD2) (a protein mediating chromosomal segregation) decreased after combination treatment which could explain the chromosomal duplication abnormalities observed. Combination treatment using lapatinib and JNK-IN-8 modulates extracellular signal-regulated kinase (ERK) phosphorylation unlike either drug alone suggesting that both JNK and ERK target G2/M check point proteins, and when perturbed, sensitize basal-type breast cancer cells to targeted therapies.
We conclude that use of specific JNK inhibitors in tumors that are resistant to lapatinib, or perhaps trastuzumab, may sensitize them to treatments with these drugs, and may also prevent resistance to these drugs in tumors that were initially responsive. Considering that JNKs are nodes in receptor tyrosine kinase and many other signaling pathways, JNK-IN-8 treatment may improve the efficacy of other targeted therapies as well.
Zhang, T. et al. “Discovery of potent and selective covalent inhibitors of JNK”. Chem Biol. 2012 Jan 27;19(1):140-54.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-17.
Abstract P6-04-21: Novel therapy of liver metastases of cancer using abraxane loaded into multi-stage nanovector
Authors: Tanei T , Liu X , Ferrari M , Godin B , Yokoi K 
Published: August 2014

Abstract
Purpose; To investigate whether the Abraxane loaded within Multi-Stage Nanovector (MSV) system (MSV-ABX) is more effective in therapy of liver metastases of breast and lung cancer as compared to Abraxane (ABX).
Experimental Design; MTT assay was performed to evaluate sensitivity of 4T1, murine breast cancer cells and 3LL, murine lung cancer cells to ABX or MSV-ABX in vitro. Experimental liver metastases were produced by intra-splenic injection of 4T1 or 3LL cells in Balb/C mice. The mice bearing liver metastases were treated with intravenous injection of (1) control (PBS), (2) ABX or (3) MSV-ABX. Then the mice were sacrificed and liver weight was measured to evaluate the therapeutic efficacy. To evaluate the biological the effects of therapeutics, we performed histological and immunohistochemical analysis of the tumor specimens. Apoptosis of 4T1 and 3LL tumor cells were evaluated by TUNEL staining, and proliferation of the tumor cells were stained using antibody to Ki67. Tumor diameter was measured in H&E stained sections.
Results; There was no significant difference in the sensitivity of 4T1 and 3LL cancer cells to ABX and MSV-ABX, in vitro. All the mice injected with 4T1 or C3LL cells developed multiple liver metastases. The liver weight was significantly lower in the mice treated with MSV-ABX as compared to those in the other groups. The tumor diameters in the liver were significantly smaller in the mice treated with MSV-ABX as compared to those in the other two groups. Immunofluorescent analysis revealed that MSV-ABX inhibited proliferation and increased apoptosis of 4T1 and 3LL tumor cells in the liver significantly more than ABX.Conclusions; These studies demonstrate that MSV-ABX is more effective than ABX in therapy of the liver metastasis of breast and colorectal cancer in our mouse models. These data can be translated into the clinic for planning novel clinical trials using MSV-ABX.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-21.
Abstract P6-05-01: Basal and induced receptor profiles cluster cell lines into subtypes and predict drug response in a panel of breast cancer lines
Authors: Schoeberl BM , Pace EA , Niepel M , Hafner M , Chai DH , Sorger PK 
Published: August 2014

Abstract
Molecular subtype is a critical determinant of therapeutic approaches in breast cancer. The subtype is based on the expression of three receptors: The Her2/ErbB2 receptor tyrosine kinase (RTK), whose over-expression defines the HER2amp subtype, and the estrogen or progesterone nuclear hormone receptors, whose over-expression defines the HR+ subtype. Triple negative breast cancers (TNBCs) express low levels of all three receptors. HER2amp status serves as a biomarker for therapy with anti-Her2/ErbB2 antibodies such as trastuzumab or pertuzumab and HR+ status is a biomarker for therapy with hormone receptor antagonists such as tamoxifen. TNBCs are usually treated with cytotoxic chemotherapy. However, breast cancer subtypes are heterogeneous, clinical and mRNA subtypes are not identical, and even the best available biomarker, HER2amp status, correctly predicts response to trastuzumab in only a subset of patients.
Projects such as the Cancer Cell Line Encyclopedia aim to identify drug response determinants by relating dose-response profiles for multiple compounds to genomic features across cancer cell collections. Recent studies have suggested that measures of target activity such as phosphorylation are more correlated with drug response than mutation status or gene expression, and steady-state protein data is becoming available for tumors and cell lines. However, few studies have tried to relate the biochemistry of signal transduction to drug response on a large scale, mainly because the measurements are demanding and the utility of the approach is unproven.
In this work, we ask whether measurement of the basal and perturbed states of immediate-to-early signaling proteins in serum-starved cells, a robust measurement that can be collected with relatively little biological variability, is predictive of tumor subtype as well as of drug response. We measured the abundance and basal phosphorylation state of nuclear and cell surface receptors and of downstream signaling kinases in the standardized NCI-ICBP43 cell line collection. Because perturbation reveals features of signal transduction that are not apparent by steady state profiling, and because biological ligands present in the microenvironment can alter drug sensitivity, we also collected response profiles by exposing cells to a diverse set of growth factors and cytokines and measuring the activities of downstream signaling kinases before and after ligand addition. We present how the resulting set of ∼3×105 receptor and cell response measurements segregated with clinical subtype and how these proteomic measurements predict the sensitivity of cells to a range of targeted anti-cancer drugs.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-01.
Abstract P6-05-02: Molecular genetic grading in breast cancer: Development and validation of a prognostic marker
Authors: Matuschek C , Boelke E , Prisack HB , Budach W , Nestle-Krämling C , Gerber PA , Pagouras C , Bojar H 
Published: August 2014

Abstract
Background: Histopathological grading is an important part for the characterization of breast cancer with regard to prognosis and treatment options. 30-60% of breast cancer patients have a grade 2 (G2) malignancy resulting in an intermediate prognosis and the challenge of finding individualized adequate treatment options. Moreover, the lack of objectivity of the grading system is criticized. With the genetic analysis of breast cancer, the deciphering of its genes and gene expression profiling using microarray technology is a new way of classifying breast cancer
Patients, Materials, and Methods. Tumor tissue from 229 breast cancer patients collected from January 2009 - June 2010 was examined. A histological grading of the tumors was determined and gene expression profiling was performed by microarray technology (Agilent Technologies). Gene expression data were reduced and a novel molecular grade index (MGI-9) was defined as a G1 versus G3 classifier by SAM (Significance Analysis of Microarray) and PAM (Prediction Analysis of Microarray). The validity of the newly defined MGI-9 as a prognostic factor was tested by applying it to three published data sets with external follow-up information for a total of 760 patients
Results: The significance analysis of gene expression profiles of 229 breast cancer patients using SAM showed more than 11,000 significantly differentially expressed genes according to the grading classes G1-2-3. The number of differentially expressed genes was reduced to 228 genes by SAM analysis using only the G1 vs. G3 cases (63 patients). PAM analysis resulted in a more reduced classifier of 44 molecular probes and we could show that a subset of 9 genes gave similar classification results and could reliably used in FFPE Material. The new MGI-9 index was tested in thee external data sets (GSE1456, GSE2034 and GSE3494) and could subdivide the histological G2 group in two molecular subgroups G2A and G2B with significant impact on survival in all test scenarios.
Conclusion: The results show that MGI 9-gene molecular grade index is more informative than the conventional histopathological grading system. In order to validate MGI-9 a prospective, randomized study with long-term follow-up for local recurrence rate and distant metastases is urgently needed.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-02.
Abstract P6-05-15: Analysis of Ki-67 index on normal breast tissue of premenopausal women exposed to tamoxifen and raloxifene: A randomized, double-blind study
Authors: Da Silva BB , Lopes-Costa PV , Rosal MA , Gebrim LH 
Published: August 2014

Abstract
Background: Raloxifene and tamoxifen were approved for breast cancer chemoprevention in women at high risk for the disease, when only clinical and epidemiological studies were considered. Nevertheless, experimental studies that compare the effects of tamoxifen and raloxifene on proliferative activity in normal breast tissue and adopt a more precise method using monoclonal antibodies (particularly Ki-67, because of its sensitivity) are scarce. Methods: A randomized, double-blind study was conducted in 57 ovulatory, premenopausal women aged 18-40 years, who had been diagnosed with fibroadenoma of the breast. The study was approved by the Internal Review Board of the Federal University of Piauí. All patients signed a written informed consent term prior to admission. The patients were divided into three statistically homogeneous groups with respect to age, tumor size, parity, and age at menarche: Group A: placebo, n = 20; Group B: tamoxifen 20 mg/daily, n = 21; and Group C: raloxifene 60mg/daily, n = 16. The study medication was administered for 22 days starting at the first day of the menstrual cycle. On the 23rd day, the fibroadenoma was removed and a sample of non-neoplastic breast tissue was collected for immunohistochemical evaluation of Ki-67 expression. A minimum of 1000 cells either stained or not with anti-Ki-67 (MIB-1) antibody were counted in each slide. For statistical data analysis (p&lt;0.05), a logistic model was used for stained cell count in relation to total cells (binomial distribution). Results: The mean percentages of Ki-67-stained nuclei in groups A, B and C were 22.16±1.91, 2.37±0.21 and 2.16±0.18, respectively (p&lt;0.001). Conclusion: Exposure to tamoxifen or raloxifene resulted in a significant and similar reduction in proliferative activity of non-neoplastic breast tissue of women of reproductive age evaluated by Ki-67 expression. Thus, further studies must be developed with the objective to validate the prophylactic effect of raloxifene in premenopausal women.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-15.
Abstract P6-05-20: Designing biomarker panels for pre- and post-menopausal breast cancer diagnostic testing using MSD technology
Authors: Henderson MC , Yeh T-F , Reese DE , Borman S , Hollingsworth A 
Published: August 2014

Abstract
At Provista Diagnostics, we have developed a breast cancer diagnostic test (dtectDx Breast) that analyzes serum levels of five protein biomarkers (IL-8, IL-12, CEA, HGF, and VEGF), which are then used in a proprietary algorithm to generate a score that can be characterized as either “normal” or “elevated”. The dtectDx Breast test has demonstrated a sensitivity/specificity of 90%/95% in a full retrospective training and validation set and 86%/87% in a recent post-market analysis. Though this test performs well in women under age 50, sensitivity and specificity both decrease when analyzing serum from women over age 50. We hypothesize that mean biomarker concentrations differ between pre-menopausal and post-menopausal women, in such a way that an ideal biomarker panel for breast cancer diagnosis in post-menopausal women may involve different analytes and a novel algorithm. To test this, we have partnered with the Mercy Women's Center in Oklahoma City to utilize prospectively-collected serum from women undergoing biopsy for a suspicious mass (all serum was drawn pre-biopsy) and from women with no evidence of a mass (to serve as a control). All patients self-reported menopausal status, thus allowing us to categorize samples as pre- or post-menopausal and determine how analyte levels vary between the populations. We determined mean concentrations for 10 protein biomarkers, all of which have previously been shown to be associated with breast cancer. All analytes were measured using Meso Scale Discovery (MSD) technology, which is highly sensitive and reliably demonstrates a low coefficient of variance between replicates. We have determined that mean serum biomarker concentrations are significantly different between pre- and post-menopausal populations in several analytes, thus suggesting that breast cancer diagnostic biomarker panels perform best when designed specifically for a target population.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-20.
Abstract P6-05-24: Expression of aquaporin 5 and its polymorphisms predict survival in patients with early breast cancer
Authors: Lee SJ , Chae YS , Park HY , Jung JH , Kim WW , Park J-Y , Jeong JY 
Published: August 2014

Abstract
Background. Our previous study showed the association of AQP5 up-regulation with cancer proliferation and migration in hormone-responsive breast cancer cell lines (MCF-7) and with unfavorable prognosis in a small number of patients with breast cancer. Accordingly, we analyzed the prognostic impact of AQP5 expression and polymorphisms in a large number of patients with early breast cancer (EBC).
Methods. AQP5 expression was investigated based on the immunohistochemistry of tissue microarray specimens from 609 EBC patients who underwent surgery between 2003 and 2008. We scored the staining intensity (IS) and percentage of positive tumor cells (PC). The genomic DNA was extracted from paraffin-embedded tumor-free tissue and then genotyped for 3 polymorphisms (rs3736309, rs1964676, and rs74091167) using the Sequenom Mass array system.
Results. Among the 3 polymorphisms, AQP5 overexpression (IS + PC ≥6) was correlated with AQP5 rs74091167 GG genotype. AQP5 overexpression and AQP5 rs74091167 was significantly associated with disease-free survival (DFS; P &lt; 0.001 and P = 0.021, respectively). Moreover, a multivariate survival analysis revealed that AQP5 overexpression and the GG genotype of AQP5 rs74091167 were significantly associated with DFS (HR = 2.026, 95% CI 1.058-3.881, P = 0.030; HR = 0.377, 95% CI 0.179-0.793, P = 0.010, respectively) adjusted to clinicopathological variables, which was prominent in patients with an ER/PgR-positive tumor.
Conclusions. Consistent with our previous study of breast cancer cell lines, AQP5 expression and AQP5 rs74091167 variant can be considered as a prognostic marker in patients with EBC after curative surgery. In the future, functional relevance of this variant needs to be clarified.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-24.
Abstract P6-06-08: Impact of initial surgical treatment delay on survival according to hormone responsiveness in breast cancer
Authors: Yoo T-K , Han W , Moon H-G , Kim J , Lee JW , Kim MK , Lee E , Kim J , Noh D-Y 
Published: August 2014

Abstract
Previous studies on the issue of the prognostic importance of treatment delay in breast cancer have shown inconsistent results. Furthermore, the association between the impact of treatment delay and molecular characteristics of tumors has not been adequately addressed. The purpose of this study is to examine the prognostic impact of initial surgical treatment delay after biopsy-proven cancer diagnosis in breast cancer patients.
A total of 1,393 consecutive invasive breast cancer patients, treated in Seoul National University Hospital, Seoul, Korea, between July 2006 and June 2008, were included in this study. Patients with in situ or metastatic carcinoma at the time of diagnosis and patients in whom the dates of the initial pathologic diagnosis were unknown were excluded.
The median time from biopsy-confirmed cancer diagnosis to initial surgical treatment was 25 days (range 0-134). When the patients were classified according to their treatment delay days (0 to 29, 30 to 59, and ≥60days), there was no difference in survival between ‘0-29days’ group and ‘30-59days’ group. However, for patients who experienced more than 60 days of initial delay in surgical treatment, the survival was significantly worse when compared to other groups (p = 0.034). The association between the treatment delay and poor outcome was only seen in patients with ER and PR negative tumors (p = 0.018) while patients with hormone-responsive tumors showed no such association. Patients with ER and PR negative tumors developed more recurrence and had shorter disease-free survival if they had treatment delay of more than 60 days. The prognostic importance of treatment delay of more than 60 days remained significant in predicting disease-free survival after adjusting for other known prognostic factors such as age, tumor size, nodal status, cancer stage, nuclear grade and Ki-67 expression (HR 5.127; 95% CI, 1.350 to 19.472; p = 0.016).
Our results suggest that having treatment delay of more than 60 days is associated with poor treatment outcome in patients with ER and PR negative breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-08.