bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A26: The metastatic potential of breast cancer cells was suppressed by NLRP3 inflammasome inhibition in macrophages
Authors: Lee Jin Y. , Lee Hye E. , Lee Joo Y. 
Published: August 2018

Abstract
Tumor microenvironment favors tumor cells to promote tumor growth, migration, invasion, and angiogenesis. IL-1beta, one of the inflammatory cytokines associated with tumor microenvironment, plays an important role in the development and progress of tumor. The activation of inflammasome is critical to secrete mature IL-1beta through stepwise reactions to activate capspase-1. Therefore, we investigated whether the metastatic potential of breast cancer cells was regulated by NLRP3 inflammasome activation of macrophages in tumor microenvironment. The activation of NLRP3 inflammasome was induced by ATP in bone marrow-derived primary mouse macrophages. The metastatic potential of 4T1 breast cancer cells was determined by migration and invasion assays with transwell system. Conditioned media from ATP-stimulated wild-type macrophages increased the migration and invasion of breast cancer cells (4T1) while conditioned media from NLRP3 knockout macrophages stimulated with ATP failed to induce the migration and invasion of breast cancer cells. Celastrol, an inhibitor of NLRP3 inflammasome, reduced the potency of macrophages to stimulate the migration and invasion of 4T1 breast cancer cells. The suppression of NLRP3 inflammasome by celastrol was mediated by the blockade of potassium efflux. The results demonstrate that the activation of NLRP3 inflammasome in macrophages leads to the enhancement of metastatic potential of breast cancer cells. The results would provide a novel anticancer strategy to modulate tumor microenvironment by suppressing NLRP3 inflammasome and consequently reducing IL-1beta production. (This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (Bio & Medical Technology Development Program, NRF-2017M3A9F5028608; Basic Research Laboratory Program, NRF-2017R1A4A1015036.)
Citation Format: Jin Y. Lee, Hye E. Lee, Joo Y. Lee. The metastatic potential of breast cancer cells was suppressed by NLRP3 inflammasome inhibition in macrophages [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A26.
Abstract A46: KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway in breast cancer
Authors: Jia Yunlu , Linbo Wang 
Published: August 2018

Abstract
Krüppel-like factor 4 (KLF4) has critical roles in breast cancer development and progression and several solid tumors. Tamoxifen (TAM) resistance represents a daunting challenge to the successful treatment of breast cancer. KLF4 expression, function, and regulation in the efficacy of TAM therapy in breast cancer have yet to be demonstrated. Here, we investigated the clinical significance and biologic effects of KLF4 in breast cancer. Firstly, higher expression of KLF4 was correlated with increased TAM sensitivity in breast cells, and analysis of GEO datasets indicated that KLF4 expression was positively correlated with ERa and enhanced expression of KLF4 sensitized breast cancer patients to endocrine therapy. Knockdown of KLF4 in MCF-7 and BCAP37 cells led to increased TAM resistance, while ectopic KLF4 expression promoted the responsiveness of MCF-7/TAM and T47D cells to TAM. Secondly, ectopic KLF4 overexpression suppressed MCF-7/TAM cell growth, invasion, and migration ability. Besides, KLF4 expression was downregulated in breast cancer tumor tissues and high expression of KLF4 linked to favorable outcome. Mechanistically, KLF4 may enhance the responsiveness of breast cancer cells to TAM through suppressing mitogen-activated protein kinase (MAPK) signaling pathway. We found that ERK and P38 were relatively activated in MCF-7/TAM compared with MCF-7, and treatment with MAPK-specific inhibitors can significantly suppress cell viability. Knockdown of KLF4 activated ERK and P38 and drove MCF-7 cells to become resistant to TAM. Conversely, overexpression of KLF4 in MCF-7/TAM cells suppressed ERK and P38 signaling and resulted in enhanced sensitivity to TAM. Therefore, our findings suggest that KLF4 contributes to TAM efficiency in breast cancer via phosphorylation modification of ERK and P38 signaling. Collectively, this study highlighted the significance of KLF4/MAPK signal interaction in regulating TAM resistance of breast cancer, and suggested that targeting the KLF4/MAPK signaling may be a potential therapeutic strategy for breast cancer treatment, especially for TAM-resistant patients.
Note: This abstract was not presented at the conference.
Citation Format: Yunlu Jia, Wang Linbo. KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A46.
Abstract A62: Canine pedigree analysis as a model of hereditary breast cancer
Authors: Lloveras-Fuentes Carlos , Goebel Katie , Merner Nancy D. 
Published: August 2018

Abstract
Genetic homology with humans and breeding practices that limit intrabreed heterogeneity make canines a useful genetic model for identifying heritable disease markers that have parallels in humans. Ultimately, the homogeneity of individual canine breeds is advantageous in identifying the modes of inheritance for human disorders that have resisted investigative efforts for decades. Particularly few genetic research studies have focused on identifying inherited risk factors for canine mammary tumor (CMT), and as such there has been little exploration of the potential overlaps between the ~65% of human hereditary breast cancer cases that are currently genetically unsolved.
DNA samples from 85 CMT-affected canines were extracted from blood/buccal swabs for whole-genome sequencing. These included 32 different canine breeds from six of the seven American Kennel Club (AKC) recognized breed groups; the most represented breeds were Golden Retrievers (n=20), Siberian Huskies (n=8), and Standard Schnauzers (n=7). The cohort also included 3 male CMT cases, which is a hallmark of hereditary CMT and comparable to hereditary breast cancer incidence in human males. Furthermore, pedigree analyses identified dogs within the CMT cohort who stem from a breed-specific common ancestor, and this indicates increased genetic homogeneity within a breed. Currently, these dogs exist in twelve different canine pedigrees corresponding to twelve different breeds and representing 72% of the CMT cohort. The most impressively linked pedigrees contain 20/20 Golden Retrievers, 7/8 Siberian Huskies, 7/7 Standard Schnauzers, 5/5 Welsh Springer Spaniels, 4/4 Newfoundlands, 4/4 Golden Setters, 3/3 Dalmatians, and 3/3 Doberman Pinschers. These CMT pedigrees highlight the characteristics of hereditary disease and demonstrate potential to identify mutations that are specific to a breed or kennel. Through pedigree analysis, fourteen samples were selected for genome sequencing, and they represented Golden Retrievers, Siberian Huskies, Standard Schnauzers, and Dalmatians. Following genome sequencing, orthologs of human genes are being investigated for comparison to human hereditary breast cancer sequencing data that were generated in our laboratory. This comparative genomics aspect may lead to the discovery of novel genes that influence breast cancer risk.
Citation Format: Anna L.W. Huskey, Carlos Lloveras-Fuentes, Katie Goebel, Nancy D. Merner. Canine pedigree analysis as a model of hereditary breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A62.
Abstract B18: ADSL controls pyrimidine metabolism and triple-negative breast tumorigenesis
Authors: Zurlo Giada , Simon Jeremy , Fan Cheng , Robinson Adam , Martinez Javier Rodriguez , Kriegsheim Alex , Locasale Jason , Perou Charles , Zhang Qing 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) represents 15% of all breast carcinomas. The unfavorable prognosis and aggressive biology of TNBC highlight the need to find new targeted therapies. Previous study from our lab has shown that the prolyl hydroxylase EglN2 contributes to TNBC progression, with its depletion leading to a decrease in TNBC cell invasion. However, the underlying mechanism remains elusive. In our current study, we developed a novel enzyme-substrate trapping strategy followed by mass spectrometry and identified adenylosuccinate lyase (ADSL) as a potential EglN2 hydroxylase substrate. EglN2 binds directly with ADSL and catalyzes ADSL hydroxylation on proline residues, which might affect ADSL activity. We demonstrated that ADSL is specifically upregulated in TNBC cell lines and patients. Functionally, depletion of ADSL led to decreased anchorage-independent growth, TNBC cell invasion, and orthotopic tumor growth. Mechanistically, integrated analyses of metabolomics and RNA-seq showed that ADSL controls pyrimidine biosynthesis that is essential for TNBC cell proliferation and invasion. Therefore, our study suggests that EglN2-ADSL signaling axis can serve as a novel therapeutic avenue in TNBC by regulating pyrimidine metabolism.
Citation Format: Giada Zurlo, Jeremy Simon, Cheng Fan, Adam Robinson, Javier Rodriguez Martinez, Alex Kriegsheim, Jason Locasale, Charles Perou, Qing Zhang. ADSL controls pyrimidine metabolism and triple-negative breast tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B18.
Abstract B36: Progesterone receptor signaling in estrogen receptor-positive breast cancer
Authors: Young Amy , Guan Jane , Daemen Anneleen , Friedman Lori , Lin Kui 
Published: August 2018

Abstract
Approximately 65% of breast cancers are estrogen receptor alpha (ERα)-positive and depend on ERα signaling for growth. Clinical data indicate that ERα-positive breast cancers have a better prognosis when another hormone receptor, the progesterone receptor (PR), is coexpressed. Recent studies show that in the presence of its ligand progesterone, PR redirects ERα chromatin binding and transcriptional activity, thereby impacting prognosis and therapeutic response.
To further examine PR function, we knocked out the PGR gene in the ERα-positive breast cancer cell lines MCF-7 and T47D using CRISPR-mediated gene editing. Knockout clones from each model were analyzed for ER- and PR-mediated transcriptional activity and gene expression profile, as well as response to selective estrogen receptor degraders (SERDs).
The T47D cell line expresses high levels of PR in the presence or absence of estrogen, and stimulation with progesterone induces robust PR phosphorylation and modulation of PR target gene expression. Furthermore, progesterone attenuates estradiol-induced cell proliferation in a dose-dependent manner. Knockout of PR in this model abrogates the ability of progesterone to induce gene expression changes or attenuate estradiol-induced cell proliferation. In contrast, the MCF-7 cell line expresses low basal levels of PR, and is refractory to stimulation with progesterone. Interestingly, in estrogenic growth media, knockout of PR in this model results in basal gene expression changes that resemble a gene signature associated with tamoxifen resistance. Consistent with these findings, knockout of PR reduces the response to SERDs in a 5-day cell proliferation assay. ChIP-seq and RNA-seq analyses are ongoing to examine how loss of PR impacts ERα chromatin binding and transcriptional output.
Citation Format: Amy Young, Jane Guan, Anneleen Daemen, Lori Friedman, Kui Lin. Progesterone receptor signaling in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B36.
Abstract B66: The conditional requirement of HER3 in HER2-amplified breast cancers
Authors: Ruiz-Saenz Ana , Dreyer Courtney , Steri Veronica , Campbell Marcia , Gulizia Nathaniel , Moasser Mark 
Published: August 2018

Abstract
The amplification and overexpression of HER2 underlies the pathogenesis of a large subset of breast, gastric, and esophageal cancers as well as smaller subsets of many other types of cancer. A substantial body of work has confirmed that overactive HER2 signaling is etiologically linked with the pathogenesis, progression and metastasis of these cancers.
HER3, the preferred heterodimerization partner of HER2, is known to be critical for HER2-amplified tumorigenesis, and this has been thought to be due to its unique ability to activate PI3K/Akt pathway. This has fueled efforts to develop HER3 targeting agents to combine with HER2 inhibitors for the treatments of these cancers, and many such agents are in the preclinical and clinical pipelines.
We have been modeling HER2-HER3 signaling co-targeting in experimental models to foresee the activities and limitations of this clinical strategy and have identified potentially significant escape mechanisms that limit the therapeutic potential of this approach. This appears to be largely due to the mistaken attribution of PI3K/Akt signaling to HER3 and the dogma that HER2 cannot activate PI3K by itself. The functions of HER3 are not entirely understood and may be partly redundant with HER2, enabling HER2 to escape the requirement for HER3. In this regard, we found that HER3-knock out HER2-overexpressing cells form tumors, and some of these tumors exhibit increased HER2 phosphorylation and Akt activation. We validated, in three different HER2-amplified cancer cell lines, that phosphorylated HER2 drives PI3K-mediated Akt activation in a HER3-independent manner. Interestingly, we found that HER2 interacts with the regulatory subunit of PI3K in these cells. We characterized this interaction and identified a tyrosine in the C-terminal tail of HER2 involved in PI3K binding. Most importantly, in vivo work demonstrates that mutation of this tyrosine reduces the transforming and tumorigenic potential of HER2-amplified cancer cells.
This work highlights that the activation of PI3K/Akt signaling by HER3 may be an important but not essential function and may ultimately be redundant with the functional capabilities of massively overexpressed HER2. Therefore, building a better understanding of the molecular mechanisms that underlie HER2-HER3-induced tumorigenesis is essential for the development of more effective therapeutic strategies.
Citation Format: Ana Ruiz-Saenz, Courtney Dreyer, Veronica Steri, Marcia Campbell, Nathaniel Gulizia, Mark Moasser. The conditional requirement of HER3 in HER2-amplified breast cancers [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B66.
Abstract IA15: PARP inhibitor resistance and acquired vulnerability in breast cancer
Authors: D’Andrea Alan D. 
Published: August 2018

Abstract
Large-scale genomic studies have demonstrated that some breast cancers, especially triple-negative breast cancers (TNBCs), harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. The most commonly altered HRR genes are BRCA1 and BRCA2, followed by other Fanconi anemia genes including FANCN/PALB2, FANCO/RAD51, FANCJ/BRIP, and FANCA. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to platinum analogues, topoisomerase inhibitors, and PARP inhibitors (PARPi). The synthetic lethal interaction with PARPi is being exploited therapeutically in diverse clinical contexts and most notably in ovarian cancer where the PARPi olaparib is FDA approved for use in patients with germline BRCA1/2 mutations. PARP inhibitor resistance has already emerged as a vexing clinical problem for the treatment of BRCA1/2 deficient tumors. The most prevalent mechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. However, PARPi resistance may still develop without restoration of HRR proficiency via disruption of multiple proteins, such as PTIP or CHD4, that leads to replication fork (RF) stabilization. Importantly, this latter mechanism—namely, the restoration of RF stability—appears to be a highly prevalent mechanism of PARP inhibitor resistance in vitro and in vivo, particularly in tumor cells with an underlying BRCA2 deficiency. Due to their underlying deficiency in BRCA2 and inability to generate RAD51 nucleofilaments, these tumor cells are unable to restore HRR mechanisms. Instead, these cells acquire PARP inhibitor resistance by limiting the nucleolytic degradation of their stalled replication forks. We have recently made the surprising observation that BRCA2-deficient tumors can become resistant to PARPi by downregulating the expression of the polycomb repressive complex PRC2, a methyltransferase complex containing EZH2, SUZ12, EED, and RbAp48. Importantly, downregulation of PRC2 results in the reduced recruitment of the nuclease MUS81 to the RF, thereby providing a novel mechanism of RF protection and PARPi resistance. A molecular understanding of PARP inhibitor resistance mechanisms may allow the generation of a new class of drugs, or a repurposing of existing drugs, which may reverse this resistance and extend the use of PARP inhibitors to more tumor types.
Citation Format: Alan D. D’Andrea. PARP inhibitor resistance and acquired vulnerability in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA15.
Abstract 13: PRMT1 as a therapeutic target in diffuse large B-cell lymphoma
Authors: Goverdhan Aarthi , Lee Heng-Huan , Havranek Ondrej , Davis Richard Eric , Hung Mien-Chie 
Published: August 2018

Abstract
Diffuse large B-cell lymphomas (DLBCL) harbor recurrent abnormalities in epigenetic regulators, such as loss-of-function mutations in EP300 and CREBBP. These include gain-of-function mutations in EZH2, largely restricted to the germinal center B-Cell (GCB) subtype. An EZH2 inhibitor EPZ-6438 showed efficacy as a single agent in phase I clinical trials in relapsed/refractory GCB-DLBCL. We examined the effect of EZH2 inhibition in GCB-DLBCL cell lines, and found an increase in histone arginine methylation in surviving cells, which was attributable to increased Type I PRMT activity. Specifically, we discovered that EZH2 inhibitors activated PRMT1, which mediated protective effects through transcriptional changes at survival genes such as BCL2, and through modulation of B-cell receptor signaling. This exciting observation suggested an opportunity for combination therapy with PRMT1 inhibitors. Since PRMT1 is poorly studied in DLBCL, we performed single-agent studies in lymphoma cell lines and discovered that inhibition of PRMT1 elicited remarkable suppression of lymphoma cell growth and viability. Analysis of gene expression data from patients indicates that PRMT1 is overexpressed in untreated DLBCL tumor samples, compared to normal B-lymphocytes. Additionally, survival analysis revealed that patients with high PRMT1 expression showed poor overall survival. These observations support the potential for combinatorial treatment with EZH2 and PRMT1 inhibitors in patients. To summarize, our studies uncover a novel epigenetic target in DLBCL, and offer avenues for improving the antitumor efficacy of EZH2 inhibitors.
Citation Format: Aarthi Goverdhan, Heng-Huan Lee, Ondrej Havranek, Richard Eric Davis, Mien-Chie Hung. PRMT1 as a therapeutic target in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 13.
Abstract IA22: Targeting CARs to the TRAC locus enhances T-cell potency
Authors: Sadelain Michel , Eyquem Justin 
Published: August 2018

Abstract
Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumor rejection. The most successful CARs used to date are those targeting CD19, which offer the prospect of complete remissions in patients with chemorefractory/relapsed B cell malignancies. CARs are typically transduced into patient T cells using γ-retroviral or other randomly-integrating retroviral vectors (RVs), which may result in variegated CAR expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific modifications in human primary cells, including site-specific transgene integration into the CCR5 and AAVS1 loci in T lymphocytes. Using CRISPR/Cas9 to edit human T cells, we have established conditions yielding efficient target gene disruption and CAR insertion in a single step. We have found that directing a CD19 CAR to the human T-cell receptor (TCR) alpha chain (TRAC) locus not only results in efficient and uniform CAR expression in human peripheral blood T cells, but, remarkably, also enhances T-cell potency, vastly outperforming that of conventionally generated CAR T cells. We further show that CAR gene expression under the control of the TCR alpha promoter minimizes tonic signaling and allows effective regulation of CAR expression. These findings provide important insights into CAR immunobiology and highlight the potential of CRISPR/Cas9 genome editing to advance immunotherapies.
Citation Format: Michel Sadelain, Justin Eyquem. Targeting CARs to the TRAC locus enhances T-cell potency [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA22.