bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-03-09: Targeting the c-myc/E2F1 pathway in TNBC promotes a DNA damage dependent synthetic lethality
Authors: Carey Jason P , Keyomarsi Khandan 
Published: May 2015

Abstract
The c-myc/E2F1 pathway is highly upregulated in TNBC and dictates increased genomic instability, a higher frequency of relapse and poor overall survival. C-myc is a potent oncogene with overexpression activity that influences several pathways including metabolism, DNA replication, DNA damage, cell cycle and apoptosis. The essential role of c-myc in normal cells has made therapeutic intervention elusive. However the role of c-myc influencing cell cycle progression has demonstrated that CDK inhibition downregulates c-myc expression in TNBC breast cancer cells. We hypothesize that CDK inhibition downregulates c-myc expression resulting in an accumulation of DNA damage thus increasing the susceptibility of TNBC cells to PARP inhibition. A panel of TNBC cell lines was assessed for c-myc/E2F1 pathway expression and downregulation in the presence of CDK inhibitor Dinaciclib. An MTT-based High Throughput Survival Assay (HTSA) was utilized to assess growth inhibition response to drug treatment in TNBC cells. FACS analysis was performed on Dinaciclib treated TNBC cell lines to asses cell cycle response to CDK inhibition. DNA damage and Homologous Recombination DNA repair was assessed by γH2AX, BRCA1, RAD51 foci formation by immunofluorescence. Lentiviral knockdown of c-myc, E2F1, BRCA1 and RAD51 were performed to assess susceptibility to PARP inhibition. Combination treatment of Dinaciclib + PARP inhibitor MK4827 was assessed via combination index values calculated by Calcusyn. CDK inhibition resulted in downregulation of both c-myc and E2F1 in all TNBC cells. The pan-CDK inhibitor Dinaciclib universally inhibited proliferation in all TNBC cell lines in the presence of the drug however drug removal allowed TNBC cells to recover a normal proliferative profile. Dinaciclib induction increased γH2AX foci formation while decreasing BRCA1 and RAD51 foci formation resulting in an increase in DNA damage induced cell death that correlated with c-myc downregulation. CDK inhibition correlated with downregulation of c-myc/E2F1 target genes. Lentiviral knockdown of c-myc and not E2F1 induced susceptibility to PARP inhibitor MK4827. Combination CDK + PARP inhibitor resulted in a dose dependent synthetic lethal increase in PARP inhibitor efficacy in both BRCA1 mutant and wild-type cells. Together these results suggest that c-myc downregulation via CDK inhibition in combination with PARP inhibition may pose a novel combination therapy for TNBC patients.
Citation Format: Jason P Carey, Khandan Keyomarsi. Targeting the c-myc/E2F1 pathway in TNBC promotes a DNA damage dependent synthetic lethality [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-03-09.
Abstract P6-05-03: CD4 Th1 cytokines and HER-2/HER-3 blockade induces tumor senescence in breast cancer
Authors: Rosemblit Cinthia , Czerniecki Brian J 
Published: May 2015

Abstract
Background: HER-2 a molecular oncodriver in breast tumorigenesis is over expressed in 25% of human breast cancers, and its expression correlates with enhanced tumor aggressiveness. While targeted therapies have improved outcomes many patients become resistant or recur. We have recently established a progressive loss in anti-HER-2 CD4 Th1 responses during disease progression and is associated with outcomes. The pleiotropic Th1 cytokines IFN-γ and TNF-α have diverse effects on tumor epithelial cells. In this study we sought to determine whether these Th1 cytokines induce senescence of HER-2 expressing breast cancer cells and assess the impact of IFN-γ and TNF-α with simultaneous HER-2 and HER-3 blockade.
Results: All breast cancer cell lines tested express IFN-γ and TNF-α receptors measured by western blot analysis. The high and intermediate HER-2 expressing cells are sensitive to tumor senescence induction when treated with combinations of IFN-γ and TNF-α in a dose dependent manner. Low HER-2 expressing cells were less sensitive to senescence induction as measured by positive β-galactosidase activity and the expression of p15INK4b and p16INK4a by western blot. Addition of IFN-γ and TNF-α treatment to HER-2-depleted cells by RNAi resulted in an increase senescent phenotype and was increased further when the cells were double HER-2- and HER-3-depleted. To determine whether CD4 Th1 mediated effects on high HER-2 human breast cancer cell lines, we co-cultured increasing number of HER-2 antigen-primed CD4+ T cells with high HER-2 human breast cancer cells in a transwell cell culture system. This resulted in a dose-dependent senescence of breast cancer cells compared with CD4+ T cells primed either with immature dendritic cells (DC) or mature DC plus irrelevant (Class II BRAF) peptide. In addition, SK-BR-3 breast cancer cells incubated with the supernatant of the CD4+ T cells-immature DC or mature DC co-culture demonstrated similar results. CD4+ Th1-elaborated cytokines IFN-γ and TNF-α in the supernatants were confirmed using ELISA. Blocking antibodies against IFN-γ and TNF-α demonstrated reduced senescence induction.
Conclusions: Our results establish a role for IFN-γ and TNF-α in inducing tumor senescence in breast cancer. An effective CD4 Th1 responses combined with HER-2 and HER-3 blockade can significantly drive tumor senescence in breast cancer that can be explored as treatment to effectively eliminate residual breast cancer cells and prevent recurrence.
Citation Format: Cinthia Rosemblit, Brian J Czerniecki. CD4 Th1 cytokines and HER-2/HER-3 blockade induces tumor senescence in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-05-03.
Abstract P6-08-20: Prognostic significance of the interferon metagene in node-negative breast cancer depends on the molecular subtype
Authors: Schmidt Marcus , van de Sandt Leonie , Edlund Karolina , Sicking Isabel , Battista Marco , Heimes Anne-Sophie , Lebrecht Antje , Hoffmann Gerald , Gehrmann Mathias , Rahnenführer Jörg , Hengstler Jan G 
Published: May 2015

Abstract
Background: Interferons are crucial for adaptive immunity and play an important role as central coordinators of tumor-immune system interactions. We examined the subtype specific prognostic significance of an interferon (IFN) metagene in node-negative breast cancer.
Methods: Using microarray based gene-expression data, we identified co-regulated genes related to biological processes. After hierarchical clustering, we defined an interferon (IFN) metagene which was composed of 36 interferon-stimulated genes. The subtype specific prognostic role of the IFN metagene was analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of the IFN metagene for metastasis-free survival (MFS) was examined in different molecular subtypes: luminal A (ER+/HER2-/aurora kinase A [AURKA]low, luminal B (ER+/HER2-/AURKAhigh), basal-like (ER-/HER2-), and HER2+.
Results: Prognostic significance of the IFN metagene was restricted to the HER2+ positive molecular subtype (HR 0.50, 95% CI 0.28-0.88, P=0.0056). Prognostic effects were not seen in luminal A (HR 1.00, 95% CI 0.65-1.53, P=0.8819), luminal B (HR 1.00, 95% CI 0.76-1.32, P=0.9770) or basal-like (HR 0.87, 95% CI 0.66-1.15, P=0.3282) carcinomas of the breast.
Conclusions: The prognostic significance of the interferon metagene in node-negative breast cancer is subtype specific and confined to the HER2+ molecular subtype. A higher expression of the IFN metagene is associated with improved outcome in HER2+ breast cancer.
Citation Format: Marcus Schmidt, Leonie van de Sandt, Karolina Edlund, Isabel Sicking, Marco Battista, Anne-Sophie Heimes, Antje Lebrecht, Gerald Hoffmann, Mathias Gehrmann, Jörg Rahnenführer, Jan G Hengstler. Prognostic significance of the interferon metagene in node-negative breast cancer depends on the molecular subtype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-20.
Abstract P6-09-05: Value of adding single-nucleotide polymorphism panel markers to phenotypic algorithms of breast cancer risk
Authors: Dite Gillian , Allman Richard , Hopper John L 
Published: May 2015

Abstract
Currently, breast cancer risk prediction algorithms incorporate phenotypic risk factors, including age, family history, reproductive history and benign breast disease.
Since 2007, genome-wide association studies have identified a growing number of single-nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. While no single SNP is very informative on its own, a polygenic approach to genetic screening could improve estimates of individual risk, creating the possibility of screening strategies individually tailored to each woman.
We studied cases and controls recruited to the Australian Breast Cancer Family Registry, to investigate whether a SNP risk score derived from a panel of 77 SNPs can improve risk estimates obtained from the commonly used breast cancer risk prediction models (BCRAT, IBIS, BRCAPRO and BOADICEA).
SNP risk scores were calculated using previously published Odds Ratios (ORs) and risk-allele frequencies based on the assumption of independence of additive risks on the log OR scale. SNP risk scores were calculated by multiplying adjusted risk scores for each of the SNPs. Combined risk scores were calculated by multiplying the SNP risk score and the algorithm derived risk scores, under the assumption of independence.
Overall, the inclusion of data on 77 SNPs improved the area under the receiver operating characteristic curve (AUC) for all of the breast cancer risk prediction models: Preliminary data analysis provided AUC values as follows: BCRAT+SNP = 0.656, IBIS+SNP= 0.628, BRCAPRO+SNP= 0.689, BOADICEA+SNP= 0.698.
The breast cancer risk prediction models examined place different weighting on the phenotypic components. For example, the IBIS model is weighted towards uncommon high-risk phenotypes, while the BCRAT is weighted towards lower risks in the general population. A combination of the 77 SNP score and the most appropriate model might substantially improve the ability to identify high-risk women in different screening populations.
Citation Format: Gillian Dite, Richard Allman, John L Hopper. Value of adding single-nucleotide polymorphism panel markers to phenotypic algorithms of breast cancer risk [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-05.
Abstract P6-09-07: The development of a prediction tool for moderate to severe diarrhea in HER-2/hormone positive metastatic breast cancer (MBC) patients receiving lapatinib in combination with letrozole (L-L)
Authors: Dranitsaris George , Locouture Mario E 
Published: May 2015

Abstract
Background: For patients with HER-2/hormone positive MBC, the addition of lapatinib to letrozole is associated improvements in tumour response rates and a prolongation of progression free survival. However, moderate to severe diarrhea (≥ grade 2) is a potentially serious toxicity which can lead to dose reductions, delays, hospitalizations and even the premature discontinuation of treatment. Patient care could substantially be improved if these diarrhea events could be accurately predicted through the use of validated and easy-to-use mathematical models. In this study, the development of a repeated measures model to predict the risk of ≥ grade 2 diarrhea prior to each month of L-L therapy is described.
Methods Data from 111 patients who received the L-L combination as part of a clinical trial were reviewed [Johnston, 2009]. Generalized estimating equations (GEE) were used to develop the final risk model using a backwards elimination process. Internal validation of the final regression coefficients was done using nonparametric bootstrapping. A risk scoring algorithm (range 0-250) was then derived from the final model coefficients. A receiver operating characteristic curve (ROC) analysis was then undertaken to measure the predictive accuracy of the final scoring algorithm.
Results: Presence of skin and lung metastases at baseline, cumulative lapatinib dose and Hg level (nadir) were identified as being important predictors for ≥ grade 2 diarrhea. There was also a negative association between time on therapy and risk of diarrhea where a higher frequency was observed in the first few months. The ROC analysis indicated good predictive accuracy with an area under the curve of 0.80 (95%CI: 0.72 – 0.88). Prior to each new month of therapy, patients with risk scores &gt; 125 units would be considered at high risk for developing ≥ grade 2 diarrhea.
Conclusions: Risk of ≥ grade 2 diarrhea is associated with cumulative lapatinib exposure, disease related factors as well as Hg level. The planned external validation and eventual clinical application of this prediction tool will be an important source of risk information for the practicing oncologist and can enhance patient care by optimizing preventative therapies earlier in a proactive manner.
Citation Format: George Dranitsaris, Mario E Locouture. The development of a prediction tool for moderate to severe diarrhea in HER-2/hormone positive metastatic breast cancer (MBC) patients receiving lapatinib in combination with letrozole (L-L) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-07.
Abstract P6-10-12: Metformin increases survival in hormone receptor-positive, Her2-positive breast cancer patients with diabetes
Authors: Kim Hee Jeong , Kwon Hyun Wook , Lee Jong Won , Lee Sae Byul , Park Hee Seung , Ahn Sei Hyun , Shin Hae Na 
Published: May 2015

Abstract
Purpose
Metformin use has recently been observed to decrease both the rate and mortality of breast cancer. Our study was aim to determine whether metformin use is associated with survival in diabetic breast cancer patients by breast cancer subtype and systemic treatment
Patients and Methods
Data from the Asan Medical Center Breast Cancer Database from 1997 to 2007 were analyzed. The study cohort comprised 6,967 nondiabetic patients, 202 diabetic patients treated with metformin, and 184 diabetic patients that did not receive metformin. Patients who were divided into three groups by diabetes status and metformin use were also divided into four subgroups by hormone receptor and HER2-neu status.
Results
In Kaplan-Meier analysis, the metformin group had a significantly better overall and cancer specific survival outcome compared with non metformin diabetic group (P &lt;0.005 for both). There was no difference in survival between the nondiabetic and metformin groups. In multivariate analysis, Compared with metformin group, patients who did not receive metformin tended to have a higher risk of metastasis with HR 5.37 (95%CI, 1.88 to 15.28) and breast cancer death with HR 6.51 (95% CI, 1.88 to 15.28) on the hormone receptor-positive and Her2-negative breast cancer. The significant survival benefit of metformin observed in diabetic patients who received chemotherapy and endocrine therapy (HR for DFS 2.14; 95% CI 1.14 to 4.04) was not seen in diabetic patients who did not receive these treatments.
Conclusion
Patients receiving metformin treatment when breast cancer diagnosis show a better prognosis only if they have hormone receptor-positive, HER2-positive tumors. Metformin treatment might provide a survival benefit when added to systemic therapy in diabetic patients.
Citation Format: Hee Jeong Kim, Hyun Wook Kwon, Jong Won Lee, Sae Byul Lee, Hee Seung Park, Sei Hyun Ahn, Hae Na Shin. Metformin increases survival in hormone receptor-positive, Her2-positive breast cancer patients with diabetes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-12.
Abstract P6-10-19: Bone mineral density(BMD) monitoring in postmenopausal women with early stage estrogen and/or progesterone receptor positive breast cancer on aromastase inhibitor(AI) therapy at University of Toledo medical center. A quality improvement project
Authors: Taj Asma , Khuder Sadik , Mohamed Iman 
Published: May 2015

Abstract
Background
More than 70% of breast cancer patients develop endocrine-responsive disease with estrogen receptor (ER)-positive or progesterone receptor-positive tumors or both [1] and require endocrine treatment with either estrogen blockage or ablation. The aromatase inhibitors are highly effective well-tolerated treatment for postmenopausal endocrine-responsive breast cancer. However, their use is associated with accelerated bone loss and an increase in fracture risk(2, 3)
Method
Post menopausal patients with early stage breast cancer( stage I and stage II) which was ER and/or PR positive and who were on AI therapy were included. Total patients 243.Stage I (101) and stage II (142).Agents used were Anastrazole, letrozole, exemestane .BMD (bone mineral density monitoring)was done by DEXA(Dual-energy X-ray absorptiometry) scan, and compared with national guidelines.
Results
243 patients were included. At 0 years(at start of AI therapy) 150(62%) did not get a DEXA scan,40(16.4%) had normal DEXA scan, 48(19.8% )had osteopenia and 5( 2%) had osteoporosis. At 2 years from AI therapy 126(51.8%) did not get a DEXA scan, 35(14.4%) had normal DEXA scan, 73(30%) had osteopenia and 9(3.7%) had osteoporosis. At 5 years from AI therapy 180(74%) did not get a DEXA scan,21(8.6%) had normal DEXA scan, 35(14.4%) had osteopenia and 7(2.8%) had osteoporosis. Anastrazole and letrozole were equally associated with osteopenia/osteoporosis. Only 50% of patients with osteoporosis(10/21) received treatment for osteoporosis.
Conclusions
Although there is evidence of negative impact of the aromatase inhibitors on bone, our data still show a poor application of the recommendations in order to prevent osteoporosis related to the administration of these drugs. Part of the problem is the mixed literature on diagnosis and management of osteoporosis. Also medicare covers for a DEXA scan only once very two years.
The national compliance for managing AI induced bone loss is very low which points out tthat this is a global problem. Our suggestion is a more active implementation of the guidelines, also by means of a greater collaboration between the oncologist and the specialist in osteoporosis, and the offer of a diagnostic and therapeutic pathway.
Citation Format: Asma Taj, Sadik Khuder, Iman Mohamed. Bone mineral density(BMD) monitoring in postmenopausal women with early stage estrogen and/or progesterone receptor positive breast cancer on aromastase inhibitor(AI) therapy at University of Toledo medical center. A quality improvement project [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-19.
Abstract P6-12-05: Inducible suppression of insulin receptor substrate I inhibits IGF-I/insulin/estradiol dependent cell growth in MCF-7L breast cancer cells
Authors: Zhang Xihong , Varma Sidhant , Yee Douglas 
Published: May 2015

Abstract
Insulin receptor substrate (IRS) proteins are adaptor proteins downstream of insulin-like growth factor (IGF) and insulin receptors. IRS proteins play a role in cancer biology, with IRS1 function linked to mitogenesis and survival and IRS2 associated with metastasis. Moreover, this family of adaptor proteins is also involved in the signal transduction of many other transmembrane receptors. Therefore IRS proteins could be potential therapeutic targets for cancer therapy. To test the function of IRS-1, we created a doxycycline inducible IRS1 shRNA and stably transfected MCF-7L breast cancer cells. The level of IRS1 protein knockdown varied within different clones from 50 to 95% reduction compared to non-induced cells. IRS2 mRNA and protein levels were not significantly affected. We chose a high (3G5) and intermediate (3A7) IRS1 knockdown clones for further study. Doxycycline treated 3G5 and 3A7, showed partial inhibition of IGF-I, IGF-II and insulin stimulated phosphorylation of IRS1(Tyr1222) and AKT. pErk1,2 were slightly increased and pIGF-IR was unchanged compared to doxycycline non-treated cells. IRS-2 tyrosine phosphorylation was stimulated when IRS-1 was suppressed and may account for the persistent downstream cell signaling. Anti IGFIR antibody dalotuzumab (20µg/ml) effectively inhibited cell signaling stimulated by IGF-I, IGF-II and insulin in both doxycycline treated and non-treated cells. There was no obvious difference in cell signaling pattern between plus and minus doxycycline treated cells within 24 hour time course. In monolayer cell growth assays, IGF-I, IGF-II, insulin and estradiol growth stimulation were significantly inhibited when IRS-1 was suppressed in 3G5 cells. In 3A7 cells, which have a lower level of IRS-1 suppression, growth stimulation was moderately inhibited. In anchorage independent growth assays stimulated by IGF-I, colony number and size were inhibited by doxycycline-induced IRS-1 suppression with a reduction of 80% in 3G5 cells and 50% reduction in 3A7 cells. These results show that growth of MCF-7L cells are dependent on IRS-1 expression. Reduced IRS1 can hinder cancer cell growth and tumorigenicity even when signaling was not impaired potentially due to compensation by other adaptor proteins. We conclude that suppression of IRS-1 may inhibit several growth regulatory pathways in breast cancer and could serve as a potential drug target.
Citation Format: Xihong Zhang, Sidhant Varma, Douglas Yee. Inducible suppression of insulin receptor substrate I inhibits IGF-I/insulin/estradiol dependent cell growth in MCF-7L breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-12-05.