bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-03-05: Model of acquired resistance to the tyrphostin NT157 in hormone receptor-positive breast cancer
Authors: Ekyalongo RC , Abdelwahab R , Holtz A , Sabet A , Yee D 
Published: May 2019

Abstract
As previously reported, the small-molecule tyrphostin NT157 binds to the type I insulin-like growth factor-1 receptor (IGF-1R) beta subunit (IGF-IRβ) resulting in degradation of the insulin receptor substrate (IRS) adaptor proteins and inhibits growth of tamoxifen sensitive and resistant ER+ breast cancer cells (Yang, Y. et al. Horm Canc, in press). To investigate effects related to long-term NT157 exposure on IGF signaling, we incubated T47D parental cells in increasing concentrations of NT157 for 20 months. This prolonged exposure resulted in resistant cells (T47D-NTR). Monolayer growth assays showed parental cells inhibited at 0.7 μM of NT157 whereas resistant cells were suppressed by 8 μM of NT157. In parental cells, NT157 caused G0-G1 arrest and an increase in the sub-G1 fraction. However, resistant cells did not show these cell cycle changes after exposure to NT157. Furthermore, the antiproliferative effect of prolonged exposure to 96 hours of NT157 was correlated with decreased activation of Akt/S6k signaling axis and reduction of cyclin D1 expression in T47D parental cells. 48 hours treatment with 5 μM of NT157 resulted in a decrease of IGF-IR and insulin receptor (InR) expression level at 33% and 39% respectively, along with the downregulation of the adaptor proteins IRS-1/2 in only the parental cell line. In resistant cells, the NT157 treatment induced minimal IGF-1R suppression and a 21% increase of IR expression. Additionally, the T47D-NTR cells-maintained IRS protein levels at 10 μM. This absence of IRS protein degradation observed in NT157-resistant cells correlated with the continued expression of estrogen receptor-alpha (ERα), suggesting functional changes within IGF and ERα complex. IGF ligands (IGF-1 or IGF-2) and estradiol (E2) stimulated growth in both cell lines. When NT157 was removed from T47D-NTR cells, they were not re-sensitized to NT157 nor were they affected by IGF dependent growth in the re-introduction of NT157. These findings suggest that resistance to NT157 is mediated by the maintained expression of the IRS adaptor proteins. The continued responsiveness to estradiol and IGF ligands could be due to either a decrease in the drug's half-life or possible changes in NT157 binding to the beta subunit of IGF-IR in resistant cells.
Citation Format: Ekyalongo RC, Abdelwahab R, Holtz A, Sabet A, Yee D. Model of acquired resistance to the tyrphostin NT157 in hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-05.
Abstract P5-03-16: KCNN4 confers multiple chemoresistance in breast cancer
Authors: Hu X , Song C-G 
Published: May 2019

Abstract
Multiple chemoresistance is a major unmet clinical obstacle in breast cancer treatment. Here, we uncovered that calcium-activated channel subfamily N member 4 (KCNN4) was an important modulator that limit the cytotoxicity of gemcitabine via a pooled ORF library screen. Importantly, elevating KCNN4 expression enhances the multiple resistance to anti-metabolism chemotherapy drugs, and accelerates cell proliferation. Conversely, silencing or using specific inhibitor, TRAM-34, can counteract its multiple chemoresistance and cell proliferative effects. Mechanically, we found that KCNN4 up-regulated BCL2A1 to suppress cell apoptosis progression via activating RAS-MAPK and PI3K-AKT signaling. In clinical specimens of breast cancer, KCNN4 expression was frequently upregulated and positively correlated with BCL2A1 expression. Moreover, high expression of KCNN4 and BCL2A1 was associated with shorten disease-free survival in studied cohorts. Collectively, our findings showed that KCNN4 was a key modulator in breast tumor progression, implicating that targeting the KCNN4 may serve as a promising therapeutic strategy to overcome multiple chemoresistance in breast cancer.
Citation Format: Hu X, Song C-G. KCNN4 confers multiple chemoresistance in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-16.
Abstract P5-04-09: Not presented
Authors: Mo H , Wang X , Qian Z , Xu B , Ma F 
Published: May 2019

Abstract
This abstract was not presented at the conference.
Citation Format: Mo H, Wang X, Qian Z, Xu B, Ma F. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-09.
Abstract P5-04-24: Molecular stratification of ER+/HER2- breast cancer cell lines to predict sensitivity to targeted agents
Authors: Bathurst L , Liao L , Crozier C , Lyttle N , Marcellus R , Bayani J , Al-awar R , Bartlett J , Spears M 
Published: May 2019

Abstract
Background: Approximately 70% of all breast cancers are estrogen receptor positive (ER+) at diagnosis and are dependent on estrogen signaling for tumour growth and proliferation. Some ER+ breast cancers can be effectively treated with adjuvant endocrine therapies including tamoxifen, but despite favorable improvements in overall survival, resistance to endocrine therapy is common and has been associated with dysregulation of several signaling pathways. These pathways can be targeted with specific inhibitors, many of which are currently under clinical investigation. However currently there is a lack of predictive biomarkers to identify which patients should receive treatment with targeted therapy. The goal of this study was to determine whether alterations in specific signaling pathways can be identified and used to stratify breast cancer cell lines to the most effective experimental treatments.
Methods/Results: Fifteen ER+/HER2- cell lines were characterized using a NanoString PAM50-like assay as well as next generation sequencing and were then stratified according to alterations in three key signaling pathways: CCND/CDK, PI3K/AKT/mTOR and FGFR. High-throughput small-molecule screenings were performed to identify the IC50 values of 24 inhibitors across the strata. Variation in inhibitor sensitivity was observed between cell lines based on molecular alterations. Cell lines with a PIK3CA mutation in combination with a CDK-pathway alteration were more sensitive to CDK inhibitors (50 to 120nM) than cell lines with alterations in the CDK-pathway alone or PIK3CA mutations alone (170nM to &gt;5000nM). In addition, cell lines with the dual alterations demonstrated stronger synergy between CDK and PI3K-pathway inhibitors compared to either alteration alone.
Conclusions: The results suggest that stratification according to molecular alterations in specific signaling pathways may predict sensitivity to targeted inhibitors in a panel of ER+/HER2- luminal breast cancer cell lines. Work is ongoing to identify the optimal synergistic inhibitor combinations for each strata. The ultimate goal is to translate this work into a novel personalized medicine approach, using molecular stratification based on a combination of molecular events in a functional pathway as opposed to single genes.
Citation Format: Bathurst L, Liao L, Crozier C, Lyttle N, Marcellus R, Bayani J, Al-awar R, Bartlett J, Spears M. Molecular stratification of ER+/HER2- breast cancer cell lines to predict sensitivity to targeted agents [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-24.
Abstract P5-05-14: Withdrawn
Authors: Elia AM , Rojas P , Liguori M , Gonzalez P , Caillet I , Martínez Vazquez P , Burruchaga J , Gass H , Lanari C 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Elia AM, Rojas P, Liguori M, Gonzalez P, Caillet I, Martínez Vazquez P, Burruchaga J, Gass H, Lanari C. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-14.
Abstract P5-05-16: Role of estrogen receptor alpha acetylation in estrogen-dependent gene regulation in breast cancers
Authors: Vasquez YM , Setlem R , Murakami S , Kraus WL 
Published: May 2019

Abstract
Estrogens, such as 17β-estradiol (E2), act through estrogen receptor alpha (ERα), a ligand-regulated transcription factor that binds across the genome to promote enhancer formation and regulate gene expression. ERα is expressed in approximately 70% of breast cancers, where it regulates the transcription of genes involved in mitogenic and inflammatory pathways. We are exploring the the acetylation of ERα on lysines 266 and 268, a modification that enhances the DNA binding and transcriptional activities of ERα. ERα acetylation is catalyzed by the lysine acetyltransferases p300 and CBP in an E2- and steroid receptor coregulator (SRC)-dependent manner. Acetylation-dependent activation of ERα has potential implications in breast cancers associated with enhanced coregulator interactions, such as SRC-3/Amplified in Breast (AIB1) gene amplifications and gain-of-function ERα mutations in endocrine resistant metastatic tumors, such as Y537S and D538G. Increased association of ERα with SRCs and p300/CBP leading to enhanced ERα acetylation may promote gain-of-function ERα activity. Our hypothesis is that acetylation of ERα alters its function by increasing E2-responsive gene transcription and signaling in breast cancers. Our current efforts are focused on investigating the role of ERα acetylation on chromatin binding and accessibility, enhancer activity, and target gene transcription. We are using the ER-positive MCF-7 breast cancer cell line with a knockdown/re-expression strategy with biochemical mimics of acetylated (K266/268Q) or unacetylated (K266/268R) ERα. Genomic ERα binding profiles using chromatin immunoprecipitation-sequencing (ChIP-seq) has defined overlapping, but unique, sets of transcriptional targets and recruitment kinetics for the ERα mutants. Current efforts are focused on defining global transcriptional responses associated with the unique binding activities using precision run-on sequencing (PRO-seq). Ultimately, our goal is to define how acetylation affects the binding of ERα to chromatin and its effect on the transcriptional activity of E2-target genes in breast cancers in the context of gain-of-function ERα mutations and coregulator amplifications. Supported in part by a postdoctoral fellowship from the Lalor Foundation to YMV, and grants from the NIDDK, NICHD, and CPRIT to WLK, as well as support from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment.
Citation Format: Vasquez YM, Setlem R, Murakami S, Kraus WL. Role of estrogen receptor alpha acetylation in estrogen-dependent gene regulation in breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-16.
Abstract P5-07-04: Not presented
Authors: Chatterjee S , Basak P , Tan S , Lefort S , Pellacani D , Safneck J , Buchel E , Aparicio S , Eaves CJ , Raouf A 
Published: May 2019

Abstract
This abstract was not presented at the conference.
Citation Format: Chatterjee S, Basak P, Tan S, Lefort S, Pellacani D, Safneck J, Buchel E, Aparicio S, Eaves CJ, Raouf A. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-04.
Abstract P5-07-12: Circular RNA NCAPG promotes breast cancer metastasis through acting as the sponge of miR-200s
Authors: He Y , Tang J 
Published: May 2019

Abstract
Background
Metastatic breast cancer remains incurable and underlying mechanisms are poorly understood. Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment that supports breast cancer metastasis. Circular RNAs are new class of endogenous noncoding RNAs. Unlike linear RNAs terminated with 5'caps and 3'tails, they uniquely have a covalently closed loop structure, making them stable and ideal candidate biomarkers. Here, we identified a circular RNA and explored for the first time how it played a dual role in epithelial to mesenchymal transition (EMT) and macrophage recruitment.
Methods
We first analyzed TCGA database about whether mesenchymal tumors could be more likely to recruit TAMs. ELISA assay was performed for determining expression level of chemokines (CSF-1, CCL2, CCL5, C5a, VEGFA, IL-34) after cell line MCF-7 finishing EMT. Next, we predicted microRNAs which could regulate CSF-1 expression and inhibit EMT using Targetscan database. Circular RNA was identified via comparing expression levels between mesenchymal-like and epithelial-like cells using circRNA microarrays. The specific mechanisms were explored via series of molecular biology assays in vitro and in vivo.
Results
Correlation analysis of relationship between EMT score and expression of all classical chemokines that could recruit macrophage revealed a positive association (r2&gt;0.3, P&lt;0.05) among 1079 breast cancer cases. Increased expression level of CSF-1 was found the most significant after EMT. miR-200b and miR-200c that inhibiting breast cancer EMT were confirmed targeting 3'UTR of CSF-1 mRNA and decreasing migration of TAMs. Circular RNA NCAPG (circNCAPG) was found highly expressed in mesenchymal-like cells and could promote breast cancer metastasis in vitro and in vivo. Poor clinical outcome was found in circNCAPG overexpression group among 141 breast cancer cases. CircNCAPG was proven to be located in cytoplasm and found could act as the sponge of miR-200b and miR-200c. Moreover, expression level of CSF-1 and ZEB-1 (also targeted by miR-200s and regulating key process of EMT) was found decreasing significantly after knocking down circNCAPG both in vitro and in vivo, leading to breast cancer metastasis inhibition.
Conclusion
Mesenchymal tumors have the ability to recruit more TAMs, therefore further promoting breast cancer metastasis. A new molecule: circNCAPG participates in this process via acting as the sponge of miR-200s and regulates CSF-1 and ZEB-1 expression, which warrants further study in clinical settings.
Citation Format: He Y, Tang J. Circular RNA NCAPG promotes breast cancer metastasis through acting as the sponge of miR-200s [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-12.
Abstract P5-08-04: Defining chromatin accessibility profiles of partial and reversible EMT
Authors: Johnson KS , Hussein S , Lin Y , Taube JH 
Published: May 2019

Abstract
The epithelial-to-mesenchymal transition (EMT) reversible cellular reprogramming event, used repeatedly throughout development, is hypothesized to be involved in the cell migration and consequently metastasis that ultimately contributes to most breast cancer-related fatalities. In this process, cuboidal epithelial cells, marked by the presence of tight junction proteins and cell-cell adhesions, lose their apicobasal polarity and acquire a spindle-like morphology and migratory traits. EMT was originally regarded to have only two states, with cells exhibiting either epithelial or mesenchymal phenotypes; however, recently, researchers have demonstrated the existence of a dual epithelial/mesenchymal state, termed hybrid- or partial-EMT. Due to its inherent plasticity, it is believed that EMT and its reversal mesenchymal-to-epithelial transition (MET) is, at least, partly regulated by epigenetic means such as alterations in chromatin structure. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) is a novel technique that employs the use of a mutant Tn5 transposase to cleave nucleosome-free DNA regions in a non-biased manner. In this investigation, we induced MCF10A mammary epithelial cells to undergo a short-term (&lt;4 days) or long-term (&gt;4 days) EMT. Addition and withdrawal of exogenous TGFβ1 produced partial- or full-EMT and MET conditions which were interrogated by ATAC- and RNA-seq. Hierarchical clustering of ATAC cleavage peaks revealed that pre-EMT and short- and long-term MET conditions demonstrate similar chromatin accessibility profiles with cleavage sites enriched for specific binding motifs. Notably, transcription factors typically not associated with EMT displayed dynamic enrichment in the accessible chromatin at various timepoints in our assay. Correlation with RNA-seq data reveals highly dynamic changes in gene expression suggesting dynamic and reversible use of regulatory programs. Importantly, partial-EMT cells were characterized by unique accessibility patterns, motif enrichment, and gene expression supporting the conclusion that this is not merely an intermediate but a unique state.
Citation Format: Johnson KS, Hussein S, Lin Y, Taube JH. Defining chromatin accessibility profiles of partial and reversible EMT [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-04.
Abstract P5-08-05: The interplay between stromal density, epithelial mesenchymal transition and chemoresistance in breast cancer
Authors: Agarwal V , Spalding LJ , Blick T , Dobrovic A , Thompson EW , Redfern A 
Published: May 2019

Abstract
Epithelial Mesenchymal Transition (EMT) refers to the transition of cells from a more differentiated epithelial phenotype to a less differentiated mesenchymal phenotype, a process that may be triggered by a range of therapeutic interventions including cytotoxic treatment, and which we have previously linked to poor breast cancer (BrCa) outcome after neoadjuvant chemotherapy (NAC)1. Mammographic breast density (MBD)represents the white radiographic appearance of epithelial and stromal breast tissue on a mammogram. High MBD in patients being treated for BrCa also associates with chemoresistance, correlating with lower pathological complete response rates (pCR)2. Linking these two stimuli, EMT can also be induced by artificial high-density stroma, where it also leads to chemoresistance in vitro3.
Here we set out to validate the link between poor outcome after NAC and EMT in a larger validatory patient cohort, and to ascertain the molecular drivers through which EMT is triggered in this setting. Further we look to confirm the association of high MBD with poor chemoresponse in the same cohort, and to assess whether this chemoresistance is mediated through EMT with the same drivers.
In a pilot cohort of 50 NAC-treated locally advanced BrCas with a pCR rate of 20%, pre-NAC biopsies and post-NAC surgical specimens were analysed for expression changes in a panel of EMT-related markers across treatment using 230 Nanostring assays. This included the EMT-driving transcription factors TWIST 1 and 2, SNAIL 1, 2 and 3 and ZEB 1 and 2, which were correlated with risk of relapse. Snail-3 showed significantly greater induction in relapsers compared to non-relapsers (OR=1.8, p=0.04) with a borderline significantly greater induction of TWIST-1 (OR=2.4, p=0.08) in relapsers in addition.
In a subsequent 240-patient validation cohort with a pCR rate of 18%, contralateral cranio-caudal view mammograms from the time of diagnosis have been collated and digitized with MBD assessment employing Cumulus software ongoing. Percent breast density will be assessed both as a continuous variable and by quartiles. Immunohistochemistry on pre- and post-operative tissue sections with pan-cytokeratin-vimentin co-staining to identify EMT and staining for SNAIL-3 and TWIST-1 is also in progress.
Associations between MBD, EMT before and after chemotherapy, pCR and relapse-free survival will be presented. The role of Snail-3 and TWIST-1 in the interplay between MBD, EMT and outcome is being explored and will be reported.
Citation Format: Agarwal V, Spalding LJ, Blick T, Dobrovic A, Thompson EW, Redfern A. The interplay between stromal density, epithelial mesenchymal transition and chemoresistance in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-05.
Abstract P5-09-14: Prevalence and type of BRCA mutations in young breast cancer patients undergoing genetic cancer risk assessment in two developing countries: Analysis of two cohorts from Romania and Mexico
Authors: Campos-Gomez S , Antone N , Pacheco-Cuéllar G , Pop L , Campos  Gomez K , Stoian A , Eniu R , Valdes-Andrade J , Dronca E , Matei R , Ligtenberg M , Ouchene H , Onisim A , Rotaru O , Eniu AE 
Published: May 2019

Abstract
Background: a previous study found significant clinicopathological differences between young Breast Cancer BrCA patients (pts) from Romania (Ro) and from Mexico (Mx). Here, we provide a molecular and clinical description of pts carrying BRCA mutations of both cohorts.
Methods: in this retrospective study, we analyzed 2 cohorts of BRCA1/2 mutations carriers tested in COEI from Mx between 2014-2017 and IOCN from Ro between 2015 to 2016. Ro pts were selected according to NCCN criteria, while Mx pts were selected based on risk evaluation models. NGS analysis and MLPA for BRCA1&2 were performed in all pts. We compared demographic, clinicopathological and molecular data.
Results: 65 pts, 21 (32.7%) from Mx and 44(67.7%) from Ro carried a BRCA mutation. 66.7% of Mx pts and 65.9% of Ro pts carried a BRCA1 mutation. We found clinical similarities: Mean age was 44.5y for Mx and 40.59y for Ro pts. IDC was the most frequent type of BrCa in both series (90.5 vs 90.9%). TNBC was seen in 13 Mx vs 27 Ro pts (61.9% vs 61.4%), HR positive was seen in 7 (33.3%) and 12 (27.3%) cases. Grading 3 was more frequently seen in Ro, while grading 2 was mainly noted in MX pts(p=&lt;0.020). BRCA1/2 pathogenic mutations were different between the 2 cohorts and no BRCA 1/2 identical mutation was identified. 15 different mutations in 21 Mx pts, and 16 different mutations in 44 Ro pts were found. Mutations were different between 2 cohorts. Notably for the Ro cohort, 4 founder mutations (c.181T&gt;G, c.3607C&gt;T, c.5266dupC in BRCA1,and c.9928A&gt;G[GPC1] in BRCA2) were found in 31/44 pts, while the Mx cohort, c.5123C&gt;A and del 9-12del ex in BRCA1 were found in 6/21 mutations. Three Large rearrangements (LR) were exclusively seen in the Mx pts (5/21).
Conclusions Both cohorts didn't share any mutation, but the clinical features are similar. BRCA1 del 9-12del is a Mexican founder mutation, we found it in 14% of Mx pts, LR have been described more frequently in Latin American Populations, we found it in 30% of the MX cohort, while for Ro cohort four recurrent mutations qualify as founder mutations.
Citation Format: Campos-Gomez S, Antone N, Pacheco-Cuéllar G, Pop L, Campos Gomez K, Stoian A, Eniu R, Valdes-Andrade J, Dronca E, Matei R, Ligtenberg M, Ouchene H, Onisim A, Rotaru O, Eniu AE. Prevalence and type of BRCA mutations in young breast cancer patients undergoing genetic cancer risk assessment in two developing countries: Analysis of two cohorts from Romania and Mexico [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-14.
Abstract P5-09-21: Not presented
Authors: Servais L , Gardner A , Gomes M , Zimmer AD , Silvestrini A , Siqueira de Abreu e Lima R 
Published: May 2019

Abstract
This abstract was not presented at the conference.
Citation Format: Servais L, Gardner A, Gomes M, Zimmer AD, Silvestrini A, Siqueira de Abreu e Lima R. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-21.