bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3591: A new method to infer clonal sequences and phylogenies from personal tumor genome profiles
Authors: Miura Sayaka , Gomez Karen , Murillo Oscar , Kumar Sudhir 
Published: July 2017

Abstract
Tumor progression involves the evolution of clonal cell populations that mutate and spread in the body. Genetic profiling has revealed the presence of extensive variation in tumor samples from individual patients. However, a tumor sample for genetic profiling is mixture of different clonal cell populations and needs to be decomposed into clonal sequences to infer the evolutionary history of the tumor. Therefore, we have developed a new method, CloneFinder, and show that the clone sequences present in each tumor sample can be accurately inferred from the analysis of multiple tumor sample profiles with our new CloneFinder method. CloneFinder is unique in its use of molecular evolutionary principles to deduce clone sequences at a single-nucleotide resolution along with their frequencies in each sample. It performs better than existing methods, which we found to produce incorrect numbers of clones, clone sequence errors, errors in clonal phylogenies, and biased estimates of cancerous cells in tumors. Application of CloneFinder to a large number of empirical datasets revealed that both early and recently evolved tumors contain ancestral clones at high frequencies. Therefore, our new method provides new insights into the clonal structure of tumors and their evolution within a personal life time.
Citation Format: Sayaka Miura, Karen Gomez, Oscar Murillo, Sudhir Kumar. A new method to infer clonal sequences and phylogenies from personal tumor genome profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3591. doi:10.1158/1538-7445.AM2017-3591
Abstract 3606: RBP2 promotes tamoxifen resistance by altering ER function and activating IGF1R and EGFR/HER2 signaling in histone methylation-dependent and -independent manners in breast cancer
Authors: Choi Hee-Joo , Son Taekwon , Kim Hyung-Yong , Min Kyueng-Whan , Oh Young-Ha , Lee Jeong-Yeon , Kong Gu 
Published: July 2017

Abstract
Retinoblastoma binding protein 2 (RBP2, also known as JARID1A), a member of the JARID1 family of histone H3 lysine K4 demethylases, has been considered to have an oncogenic potential in several types of human cancers including breast cancer. Although physical interaction between RBP2 and estrogen receptor (ER), a crucial factor for hormone-dependent breast cancer, has been implied, the role of RBP2 in ER-positive (ER+) breast cancer remains largely unknown. Here, we demonstrate that RBP2 is a novel therapeutic target for tamoxifen resistance in ER+ breast cancer as an ER co-regulator and an activator of receptor tyrosine kinase (RTK) signaling. In large cohorts of breast cancer patients including METABRIC, high expression of RBP2 was associated with poor response to tamoxifen therapy in ER+ breast cancer. Consistently, RBP2 induced tamoxifen resistance in ER+ breast cancer both in vitro and in vivo. Using RNA-sequencing analysis, we identified that many RBP2 target genes are overlapped with ER-dependent- and tamoxifen resistance-associated genes. Mechanistically, RBP2 induced not only hyperactivation of ER-dependent transcription but also estrogen agonist activity of tamoxifen-bound ER via the interaction with ER, thus increasing the expression of NRIP1, a co-repressor of ER. RBP2 also formed a transcriptional repressive complex with ER, NRIP1, and HDAC1 to induce H3K4 demethylation-mediated epigenetic gene silencing of IGFBP4 and IGFBP5, leading to the activation of IGF1R and its downstream, PI3K/AKT pathway. Furthermore, enhanced AKT phosphorylation by RBP2 was mediated by not only IGF1R but also EGFR/HER2 signaling via increasing the stability of EGFR and HER2 proteins in a demethylase activity-independent manner. We further confirmed that combinational treatment with tamoxifen and PI3K inhibitor BKM120 restored tamoxifen sensitivity in RBP2-overexpressing breast cancer. Taken together, these findings suggest that RBP2 mediates tamoxifen resistance in ER+ breast cancer by altering ER activity and activating IGF1R and EGFR/HER2 signal pathways in both a histone methylation-dependent and -independent manner. Therefore, RBP2 may be a promising prognostic marker and therapeutic target for endocrine therapy-resistant breast cancer.
Citation Format: Hee-Joo Choi, Taekwon Son, Hyung-Yong Kim, Kyueng-Whan Min, Young-Ha Oh, Jeong-Yeon Lee, Gu Kong. RBP2 promotes tamoxifen resistance by altering ER function and activating IGF1R and EGFR/HER2 signaling in histone methylation-dependent and -independent manners in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3606. doi:10.1158/1538-7445.AM2017-3606
Abstract 3617: A paradigm shift for insulin-like growth factor 1 receptor function in triple negative breast cancers
Authors: Obr Alison , Kumar Sushil , Birge Raymond , Wood Teresa 
Published: July 2017

Abstract
Signaling through the insulin-like growth factor type 1 receptor (IGF-1R) is complex in breast cancers. Early studies reported that expression of the IGF-1R correlated with estrogen receptor (ER) expression and predicted a favorable phenotype. Moreover, loss of IGF-1R has been associated with breast tumor progression into a more undifferentiated phenotype. We have generated and characterized a mouse line containing both MMTV-Wnt1 and MMTV-dnIGF-1R (kinase dead-IGF-1R) transgenes (referred to subsequently as bigenic mice) that leads to increased mammary tumor initiation and metastasis. These data support the hypothesis that the IGF-1R functions in suppressing metastasis in certain contexts and subtypes of triple negative breast cancers (TNBCs). Recent analyses of TCGA human datasets support the relevance of our model in human TNBCs that have reduced IGF-1R expression and increased expression of Wnt1 and the Frizzled co-receptor Lrp6. We have identified alterations in a number of target genes that potentially regulate metastasis in the bigenic primary tumors including increases in interleukin-6 (IL-6), Slug, Vimentin, Zeb 1/2 and decreases in E-cadherin expression as assessed by Qiagen specific qPCR and single gene qPCR. Furthermore, a subset of anti-inflammatory chemokines and cytokines were assessed by a targeted qPCR array revealing increases in interleukin-4, interleukin-10, and C-C motif chemokine ligand-2 and decreases in tumor necrosis factor-alpha in the bigenic tumors indicating a tumor associated macrophage phenotype. By flow cytometry analysis, the ratio of CD4+ T cells to CD8+ T cells is increased in the bigenic tumors suggesting a tumor promoting immune microenvironment. However, increased expression of IL-6 in the bigenic tumors is specific to the luminal tumor cells, and inhibition of IGF-1R in the MCF7 human breast cancer cell line results in increases in IL-6, Slug, and Zeb 1/2 expression suggesting the tumor cells activate EMT and a pro-tumorigenic microenvironment in response to decreased IGF-1R. Moreover, inhibition of IGF-1R in human breast cancer cells and MMTV-Wnt1 mouse tumor cells results in increased cell motility and invasion as assessed by the xCELLigence motility assay. Taken together, our data support the hypothesis that IGF-1R acts as a negative regulator of mediators that promote migration, invasion, and metastasis in TNBCs.
Citation Format: Alison Obr, Sushil Kumar, Raymond Birge, Teresa Wood. A paradigm shift for insulin-like growth factor 1 receptor function in triple negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3617. doi:10.1158/1538-7445.AM2017-3617
Abstract 3618: PELP1 cytoplasmic mislocalization favors estrogen-induced signaling via AIB1 in ER+ breast cancer models
Authors: Truong Thu H. , Ostrander Julie H. , Lange Carol A. 
Published: July 2017

Abstract
Luminal breast cancers account for ~75% of cases and express (ER) and frequently contain a range of progesterone receptor (PR) positive cells. ER and PR are steroid hormone receptors (SR) that rapidly and dynamically shuttle between the cytoplasm and the nucleus, a process that allows for essential crosstalk with cytoplasmic signaling pathways that serve as direct inputs to SR transcriptional functions. During disease progression, aberrant hormone signaling often leads to expression of altered SR gene programs and endocrine resistance. An emerging biomarker of increased risk and aggressive cancer behavior is cytoplasmic PELP1. Our lab was the first to show that PELP1 forms a functional signaling and transcriptional complex with ER and PR to regulate novel estrogen-driven SR target genes associated with endocrine resistance. PELP1 is primarily nuclear in normal breast tissue, but cytoplasmic localization of PELP1 (cyto-PELP1) is observed in 40-58% of invasive tumors. To elucidate the impact of PELP1 mislocalization on SR signaling pathways and transcription programs, we have generated SR+ breast cancer cell models expressing vector, wild-type (nuclear) PELP1, and cyto-PELP1. Our studies show that cells expressing cyto-PELP1 exhibit increased mammosphere formation relative to WT-PELP1 or vector control cells in response to estrogen. Moreover, we have identified AIB1 (ER co-activator) as a robust binding partner for cytoplasmic, but not nuclear PELP1, through mass spectrometry. This interaction occurs in a hormone-dependent manner as shown by co-immunoprecipitation assays. AIB1 activation (i.e. phosphorylation levels) is increased in cyto-PELP1 cells relative to WT-PELP1 or control cells. Knockdown of AIB1 reduces cyto-PELP1 protein levels and leads to decreased gene expression of key pro-inflammatory and immune regulatory cyto-PELP1 target genes. Our results reveal novel cytoplasmic actions of AIB1 and highlight the significance of delineating the impact of dynamic PELP1 shuttling/mislocalization with respect to altered hormone/SR-driven target gene expression in luminal breast cancer progression. We conclude direct signaling inputs to SR complexes are profoundly altered in the context of PELP1 mislocalization and interaction with AIB1. Our findings are relevant to mechanisms of endocrine resistance that may be targeted by inhibitors of the PELP1/SR interaction.
Citation Format: Thu H. Truong, Julie H. Ostrander, Carol A. Lange. PELP1 cytoplasmic mislocalization favors estrogen-induced signaling via AIB1 in ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3618. doi:10.1158/1538-7445.AM2017-3618
Abstract 362: Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma
Authors: Makino Yojiro , Yoon Jeong-Hwan , Bae Eunjin , Kato Mitsuyasu , Miyazawa Keiji , Ohira Tatsuo , Ikeda Norihiko , Kuroda Masahiko , Mamura Mizuko 
Published: July 2017

Abstract
Cancer-associated inflammation develops resistance to the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) harboring oncogenic EGFR mutations. Stat3-mediated Interleukin (IL)-6 signaling and Smad-mediated transforming growth factor-β (TGF-β) signaling play crucial regulatory roles in cancer-associated inflammation. Here we show that Stat3 represses Smad3 in cooperation with c-Ski and SnoN, whereby renders gefitinib-sensitive HCC827 cells resistant. IL-6 signaling via phosphorylated Stat3 induced gefitinib resistance. By contrast, TGF-β upregulated gefitinib sensitivity. We found that IL-6 signaling via phosphorylated Stat3 repressed, whereas TGF-β upregulated the expression of Smad3 in HCC827 cells. Promoter analyses showed that Stat3 synergized with c-Ski/SnoN to repress Smad-induced transcription of the Smad3 gene. Smad3 induced apoptosis by upregulating pro-apoptotic genes such as Caspase 3 and downregulating anti-apoptotic genes such as Bcl2. Our results suggest that preventing IL-6/Stat3-induced loss of Smad3 can be a therapeutic strategy to prevent gefitinib resistance in NSCLCs with gefitinib-sensitive EGFR mutation.
Citation Format: Yojiro Makino, Jeong-Hwan Yoon, Eunjin Bae, Mitsuyasu Kato, Keiji Miyazawa, Tatsuo Ohira, Norihiko Ikeda, Masahiko Kuroda, Mizuko Mamura. Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 362. doi:10.1158/1538-7445.AM2017-362
Abstract 3621: Characterization of the effects of estrogen receptor alpha Y537S and D538G mutations on receptor pharmacology
Authors: Hartman Steven J. , Kleinheinz Tracy , White Jonathan , Daly Stephen , Goodwin Ria , Zhou Wei , Liang Jun , Wang Xiaojing , Ortwine Daniel F. , Friedman Lori , O’Rourke Martin , Metcalfe Ciara , Blake Robert A. 
Published: July 2017

Abstract
The frontline therapy for estrogen receptor alpha (ERα) positive Breast Cancer (ER+BC) involves various forms of endocrine therapy, consisting of either Selective Estrogen Receptor Modulators (SERMs) or aromatase inhibitors. An emerging mechanism of ER+BC resistance to endocrine therapy, and consequently disease relapse, has been associated with a set of “hotspot” mutations in and near to helix-12 of the ERα ligand binding domain. Selective Estrogen Receptor Degraders/Down-regulators (SERDs) represent an important pharmacological strategy being applied to develop treatments for resistant ER+BC. Here, we compare 2 of the most frequent ERα hotspot mutations (Y537S and D538G), with ERα wildtype (WT) and the ability of a set of SERM/SERDs and other ERα ligands to bind, antagonize, degrade/stabilize ERα and affect cell proliferation. Common themes that emerged included the observation that the concentration of each drug required to bind, antagonize or degrade ERα Y537S or ERα D538G was typically higher than that required for ERα WT, although the extent of the shift varied between drugs and the type of measurement. An unexpected observation was that 4-hydroxy-tamoxifen (a major active metabolite of tamoxifen) stabilized nuclear ERα Y537S protein. This represents a potential mechanism that may limit the efficacy of Tamoxifen in treating ERα Y537S ER+BC.
Citation Format: Steven J. Hartman, Tracy Kleinheinz, Jonathan White, Stephen Daly, Ria Goodwin, Wei Zhou, Jun Liang, Xiaojing Wang, Daniel F. Ortwine, Lori Friedman, Martin O’Rourke, Ciara Metcalfe, Robert A. Blake. Characterization of the effects of estrogen receptor alpha Y537S and D538G mutations on receptor pharmacology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3621. doi:10.1158/1538-7445.AM2017-3621
Abstract 3623: Preclinical efficacy of the selective GR antagonist, CORT125134
Authors: Hunt Hazel , Belanoff Joseph , Block Thad , Shepherd Stacie P. 
Published: July 2017

Abstract
The role of activation of the glucocorticoid receptor (GR) in the response of several solid tumor types to chemotherapy has been reported by several groups. Skor et al1 have demonstrated that the non-selective GR antagonist mifepristone can potentiate the effect of paclitaxel in a mouse xenograft derived from a human triple negative breast cancer (TNBC) cell line. GR activation is thought to play a role in the regulation of pro- and anti-apoptotic genes. Isikbay et al2 have demonstrated the benefits of combining androgen deprivation therapy with GR antagonism in prostate cancer xenograft model. Signaling via GR appears to be able to compensate for lack of androgen receptor signaling, and to contribute to castrate resistance.
CORT125134 is a novel, selective GR antagonist being developed for the treatment of a variety of solid tumors, in combination with an appropriate standard of care agent. CORT125134 is currently being studied in a Phase1/2 study in solid tumors, in combination with nab-paclitaxel.
The efficacy of CORT125134 in combination with standard of care agents has been investigated in mouse xenograft models of several tumor types. Previous reports of the benefit of adding a GR antagonist to chemotherapy in a TNBC model and an ovarian cancer model have been confirmed. An enhancement of the anti-tumor effect of castration by the addition of a GR antagonist has been confirmed in a model of prostate cancer. In addition, CORT125134 has been shown to provide a significant improvement in the efficacy of paclitaxel in a pancreatic cancer model. In a MIAPaca-2 xenograft model, paclitaxel was given i.v. every 4 days either alone or in combination with CORT125134. The combination provided significantly better tumor group inhibition than paclitaxel alone (p&lt;0.0001). These encouraging results in a pancreatic cancer model extend the potential utility of GR antagonism in a variety of solid tumor types. In the TNBC model, alternative dosing regimens have been investigated, and suggest that stress during dosing is a confounding factor in these studies.
1. Skor MN, Wonder E, Kocherginsky M, et al. Glucocorticoid receptor antagonism as a novel therapy for triple negative breast cancer. Clinical Cancer Res. 2013;19(22):6163-6172.
2. Isikbay M, Otto K, Kregel S, et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer. 2014;5(2):72-89.
Citation Format: Hazel Hunt, Joseph Belanoff, Thad Block, Stacie P. Shepherd. Preclinical efficacy of the selective GR antagonist, CORT125134 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3623. doi:10.1158/1538-7445.AM2017-3623
Abstract 3625: Thyroid hormone, thyroxine, promotes cell proliferation and β-catenin activation in colorectal cancer
Authors: Lee Yee-Shin , Hsieh Meng-Ti , Chin Yu-Tang , Hercbergs Aleck , Davis Paul J. , Wu Han-Chung , Lin Hung-Yun 
Published: July 2017

Abstract
Backgrounds: Being a crucial hormone regulating growth, metabolism and various physiological processes, the status of thyroid hormone has long been implicated in cancer risks and tumor developments. In the present study, we aimed to look at the role of thyroid hormone, thyroxine (T4), in colorectal cancer cell proliferation and β-catenin activation, which is highly involved in both normal and oncogenic developments of the gut.
Materials and Methods: The effects of T4 in colorectal cancer cell lines HCT 116 (APC wild type) and HT-29 (APC mutant) as well as the primary cells derived from colorectal cancer patients were studied. Cell proliferation was evaluated according to cell counting, MTT assay and qRT-PCR. The activation of β-catenin was examined using Western blotting, qRT-PCR and immunoprecipitation.
Results: The results showed that T4 increased the cell number of both HCT 116 and HT-29 cells compared to the untreated cells. In both cell lines, T4 induced nuclear β-catenin accumulation and the protein levels of WNT/β-catenin targets Cyclin D1 and c-Myc. The mRNA expression of CTNNB1 was elevated by T4 in HCT 116 cells, but not in HT-29 cells. In APC wild type HCT 116 cells, T4 increased the WNT4 mRNA expression and decreased the association between β-catenin and the WNT-regulated β-catenin destruction complex. Moreover, the cell numbers of T4-treated primary cells were higher compared to the untreated cells while the mRNA expressions of proliferative genes PCNA, CCND1 and c-Myc were elevated by T4. In the primary cells, T4-induced nuclear β-catenin accumulation, protein levels of Cyclin D1 and c-Myc, and mRNA expressions of CTNNB1 and WNT4 were also observed.
Conclusions: T4 promoted cell proliferation and β-catenin activation in colorectal cancer. In the cells with different APC mutation status, the activation of β-catenin was regulated by different mechanisms.
Citation Format: Yee-Shin Lee, Meng-Ti Hsieh, Yu-Tang Chin, Aleck Hercbergs, Paul J. Davis, Han-Chung Wu, Hung-Yun Lin. Thyroid hormone, thyroxine, promotes cell proliferation and β-catenin activation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3625. doi:10.1158/1538-7445.AM2017-3625
Abstract 3632: BiTE® antibody constructs for the treatment of SCLC
Authors: Giffin Michael J. , Lobenhofer Ed K. , Cooke Keegan , Raum Tobias , Stevens Jennitte , Beltran Pedro J. , Coxon Angela , Hughes Paul E. 
Published: July 2017

Abstract
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with a poor prognosis and limited therapeutic options. Most patients present with extensive stage disease, where recent advances in immunotherapies, including bi-specific T cell engager (BiTE®) antibody constructs, represent a promising new therapeutic approach. BiTE® molecules have demonstrated durable complete responses in the clinic in hematological malignancies. Similar to hematological malignancies, SCLC is also a widely-disseminated malignancy that shows very high response rate to first line therapies with high rates of disease recurrence, features which may support efficacy of the BiTE® modality. Next generation sequencing (NGS) identified Delta-like Ligand 3 (DLL3) as a highly specific tumor associated antigen for SCLC, with consistent expression in tumors and very low expression in normal tissues. Tumor expression of DLL3 protein was confirmed by IHC, with 30 of 35 SCLC tumors staining positive for DLL3. DLL3 BiTE® antibody constructs showed low pM potency in vitro and also demonstrated significant inhibition of tumor growth in vivo in an orthotopic model of SCLC. A half-life extended (HLE) BiTE® targeting DLL3 demonstrated antibody-like pharmacokinetic properties in single-dose studies in non-human primates (NHP), with a half-life of 11 days. This is predicted to support every other week dosing in humans. The combination of high potency and excellent PK properties suggests that HLE BiTE® molecules may provide a useful tool for targeting residual disease in SCLC patients whose tumors express DLL3.
Citation Format: Michael J. Giffin, Ed K. Lobenhofer, Keegan Cooke, Tobias Raum, Jennitte Stevens, Pedro J. Beltran, Angela Coxon, Paul E. Hughes. BiTE® antibody constructs for the treatment of SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3632. doi:10.1158/1538-7445.AM2017-3632