bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3107: Runt-related transcription factor 1 (RUNX1) is involved in transcriptional repression by estrogen receptor and breast cancer cell proliferation.
Authors: Liu Ka , Smith Richard L. , Nguyen-Vu Trang , Candelaria Nicholes R. , Rogerson Colin M. , Johnson W. Evan , Cheung Edwin , Jankovic Boris R. , alawi Wail Ba , Zhang Jinsong , Bajic Vladimir B. , Lin Chin-Yo 
Published: August 2014

Abstract
In the majority of breast cancers, estrogen and its cellular receptor, estrogen receptor (ER), are involved in regulating tumor cell proliferation. ER is both a prognostic marker and a therapeutic target in the management of hormone-dependent tumors. Current research efforts and the paradigm of ER transcriptional regulatory functions in breast cancer have focused on the role of ER in activating target gene transcription. Microarray studies and whole-genome ER binding site mapping experiments indicate, however, that ER can alternatively directly repress the expression of a significant subset of target genes. We posit that transcriptional repression by ER likely involves interactions with other co-regulatory transcription factors found in the proximity of ER binding sites in the cis-regulatory regions of repressed target genes and have identified the runt-related transcription factor 1 (RUNX1), a key regulator of hematopoiesis and leukemogenesis, as a candidate co-regulatory factor involved in transcriptional repression by ER. Here, we demonstrate that RUNX1 interacts with ER, specifically the ligand-binding domain, and is involved in the repression of ER target genes and estrogen-dependent and -independent proliferation of breast cancer cells. We also show that putative ER-RUNX1 target genes are associated with disease outcome in breast cancer patients. These findings not only provide the first evidence for the involvement of RUNX1 in hormonal carcinogenesis and additional insights into mechanisms of transcriptional regulation by ER but may potentially lead to more effective strategies for targeting ER and estrogen signaling in the prevention and treatment of breast cancer.
Citation Format: Ka Liu, Richard L. Smith, Trang Nguyen-Vu, Nicholes R. Candelaria, Colin M. Rogerson, W. Evan Johnson, Edwin Cheung, Boris R. Jankovic, Wail Ba alawi, Jinsong Zhang, Vladimir B. Bajic, Chin-Yo Lin. Runt-related transcription factor 1 (RUNX1) is involved in transcriptional repression by estrogen receptor and breast cancer cell proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3107. doi:10.1158/1538-7445.AM2013-3107
Abstract 3108: A novel role for hPygo2 in ribosomal RNA transcription.
Authors: Andrews Phillip G. P. , Kao Kenneth R. 
Published: August 2014

Abstract
Background: Several ribosomes are required for each translated messenger RNA. During cell growth and division, a significant proportion of cellular resources are devoted to the production of ribosomes, but the epigenetic mechanisms by which cells adjust to this requirement are not fully understood. We have previously demonstrated that human Pygopus 2 (hPygo2) is highly expressed in, and required for the growth of a number of different cancers. hPygo2 functions as a chromatin remodeling protein through direct association with trimethylated Histone H3 at lysine4 (H3K4me3). It is here that hPygo2 likely serves as an adapter to which histone acetyltransferases can bind and promote further chromatin remodeling events required for transcription. We now present evidence that hPygo2 is involved in chromatin remodeling at the ribosomal (r)RNA promoter during proliferative growth of cancer cells. Methods: Immunoprecipitation (IP) and immunofluorescence (IF) was performed in breast (MCF7), ovarian (SKOV3) and cervical (HeLa) cancer cells. siRNAs were designed to specifically deplete hPygo2. For hPygo2 binding to the ribosomal gene promoter, chromatin IPs were used and analyzed by conventional or quantitative (q) PCR. 47S rRNA expression was measured by qPCR or by pulse-chase with either Br-UTP or 3H-uridine. Cell cycle analysis was performed by flow cytometry. Results: We found that hPygo2 interacted with UBF-1 and Treacle, two nucleolar proteins involved in 47S rRNA transcription. hPygo2 co-localized with UBF-1 and Treacle along with newly synthesized de novo rRNA in the nucleoli of cancer cells. hPygo2 was further detected at the ribosomal gene promoter along with core components of the rDNA transcription complex, including RNA polymerase I. Furthermore, hPygo2 was required for Histone H4 acetylation at the rRNA promoter and for transcription of the 47S pre-rRNA. Depletion of hPygo2 was accompanied by activation of the ribosomal stress response, detected by the binding of ribosomal protein L11 to hdm2, thereby inhibiting its E3 ubiquitin ligase activity resulting in p53 dependent growth arrest. Conclusion: Our results suggest that chromatin remodeling function of hPygo2 may serve to augment or maintain 47S pre-rRNA transcription required for ribosome biogenesis in cancer.
Citation Format: Phillip G. P. Andrews, Kenneth R. Kao. A novel role for hPygo2 in ribosomal RNA transcription. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3108. doi:10.1158/1538-7445.AM2013-3108
Abstract 3111: Expression of chromobox homolog 7 (Cbx7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via regulating TRAIL-induced apoptotic pathway.
Authors: Yamashita Yoriko , Shinjo Kanako , Yamamoto Eiko , Akatsuka Shinya , Takahashi Takashi , Kajiyama Hiroaki , Kikkawa Fumitaka , Toyokuni Shinya 
Published: August 2014

Abstract
Ovarian cancer is the most lethal gynecologic malignancy, and among them, clear cell adenocarcinoma of the ovary (OCCA) has relatively worse prognosis associated with chemoresistancy. Chromobox (Cbx) 7 is a component of the polycomb repressive complex 1 that prolongs the lifespan of normal human cells via down-regulating the expression of INK4a/ARF and thus related with cell-cycle progression. However, recent reports studying the relationship between Cbx7 expression and the patient's survival differs among the cell origins of the tumors, and the precise role of Cbx7 in human carcinomas remains obscure. In this study, we analyzed the expression of Cbx7 by immunohistochemistry in 81 OCCA patients and evaluated the association with their clinical outcome. Both overall survival and progression-free survival of the patients were significantly shorter in Cbx7-positive than Cbx7-negative (P&lt;0.05) tumors in OCCA. Cbx7 knockdown experiments using two OCCA cell lines, TOV21G and KOC-7C, revealed that the viability of the cells were significantly reduced compared to control (P&lt;0.001). Expression microarray analysis revealed that apoptosis-related genes, especially TRAIL, were significantly upregulated in Cbx7 knockdown cells (P&lt;0.01). We further confirmed that Cbx-7 knockdown resulted in TRAIL-induced apoptosis in OCCA cells. Thus, in this study, we showed for the first time that Cbx7 is associated with worse prognosis in OCCA. We also successfully demonstrated that the TRAIL pathway is a novel target of Cbx7 in these cells, and therapeutic agents utilizing the TRAIL pathway may be specifically effective targeting OCCA.
Citation Format: Yoriko Yamashita, Kanako Shinjo, Eiko Yamamoto, Shinya Akatsuka, Takashi Takahashi, Hiroaki Kajiyama, Fumitaka Kikkawa, Shinya Toyokuni. Expression of chromobox homolog 7 (Cbx7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via regulating TRAIL-induced apoptotic pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3111. doi:10.1158/1538-7445.AM2013-3111
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3114: Constitutively active signal transducer and activator of transcription-3: an oncogene that increases gap junctional intercellular communication.
Authors: Trotman-Grant Aaron , Geletu Mulu , Raptis Leda 
Published: August 2014

Abstract
Gap junctions are specialized intercellular channels that connect the cytoplasm of adjacent cells and mediate the direct exchange of small ions and molecules between them. Gap junctional intercellular communication (GJIC) is usually blocked, or downregulated, in cells transformed by oncogenes, such as Src. One of the Src effector pathways leading to transformation and GJIC suppression is the Ras/Raf/MEK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathway that has a prominent etiological role in cell proliferation, differentiation and cell survival; inhibition of this pathway in vSrc transformed cells restores GJIC. In addition, the distinct downstream effector of Src that is obligatory for neoplasia is the signal transducer and activator of transcription-3 (Stat3). Stat3 has the intrinsic characteristic of being upregulated in a range of tumors, and a modified version, the constitutively active form of Stat3 (Stat3C), has been shown to function as an oncogene. Conversely, inhibition of Stat3 can suppress tumor growth. To examine the role of Stat3 upon the Src-mediated, GJIC suppression, Stat3 was downregulated in rat liver epithelial T51B cells expressing activated Src through treatment with the CPA7, Stat3 inhibitor, or through infection with a retroviral vector expressing a Stat3-specific shRNA. The extent of GJIC was determined by electroporating the fluorescent dye, Lucifer yellow, into cells grown on two co-planar electrodes of electrically conductive, optically transparent, indium-tin oxide, followed by observation of the migration of the dye to the adjacent, non-electroporated cells under fluorescence illumination. The results demonstrate that, contrary to inhibition of the Ras pathway, Stat3 inhibition in cells expressing activated Src does not restore GJIC. On the contrary, Stat3 inhibition in normal cells with high GJIC levels eliminated junctional permeability. Interestingly, our results also demonstrate that expression of Stat3C in T51B cells and human lung cancer SK-LuCi6 cells, which have extensive communication and low Src levels, increased GJIC. Therefore Stat3, although it is generally growth promoting and in an activated form can act as an oncogene, its function is actually required for and increases junctional permeability.
Citation Format: Aaron Trotman-Grant, Mulu Geletu, Leda Raptis. Constitutively active signal transducer and activator of transcription-3: an oncogene that increases gap junctional intercellular communication. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3114. doi:10.1158/1538-7445.AM2013-3114
Abstract 3121: c-Jun as a target in pancreatic cancer.
Authors: Sheahan Anjali V. , Khachigian Levon M. 
Published: August 2014

Abstract
Prognosis for pancreatic cancer is especially poor, with a 5% survival rate. Current FDA-approved therapeutics gemcitabine and erlotinib extend patient survival by a mere two months. As the disease is asymptomatic, patients are generally diagnosed at later stages of the disease. Consequentially, only 15-20% of patients present with resectable tumors. Further, aggressive metastasis often occurs after surgical intervention, resulting in the death of 75% of patients within five years. These statistics indicate an unmet need for more effective therapeutic strategies to combat pancreatic cancer.
c-Jun is a component of the AP-1 early response transcription factor. It is expressed in 87% of primary pancreatic cancer lesions and in several pancreatic cancer cell lines. c-Jun overexpression has been linked to metastasis in numerous cancer models and previous work in our laboratory has demonstrated the efficacy of a DNAzyme against c-Jun for the suppression of tumor growth and angiogenesis in in vivo models of basal and squamous cell carcinoma. We sought to explore the role of c-Jun in pancreatic cancer and the therapeutic potential of gene silencing of endogenous c-Jun.
We confirmed serum-inducible c-Jun expression at the mRNA level using qRT-PCR in two in vitro models of pancreatic adenocarcinoma, PANC-1 and MIA PaCa-2. This is consistent with Western blot data, which confirm expression of both c-Jun as well as its phosphorylated form (p-c-Jun) at the protein level. Optimal uptake of a FITC-labeled siRNA into these cell lines was achieved using DOTAP/DOPE transfection reagent. We subsequently demonstrated that the effective blockade of c-Jun and p-c-Jun could be achieved with siRNA targeting human endogenous c-Jun. At the functional level, while blockade of c-Jun had no apparent effect on cell proliferation, PANC-1 and MIA PaCa-2 cell migration and invasion were markedly reduced. This was demonstrated using transwell assays. Interestingly, this effect was enhanced in cells that were also treated with gemcitabine. Further, we showed that MMP-1 expression was inhibited in MIA PaCa-2 cells treated with siRNA targeting c-Jun. We have also identified Cystatin F, MDM2, MET, MMP-13 and NF2 as potential downstream targets of c-Jun using a human tumor metastasis PCR array.
This in vitro data confirms the expression and activation of c-Jun in pancreatic cancer cells, and demonstrate a functional role for c-Jun in pancreatic cancer cell migration and invasion, which underpin metastasis. We are in the process of validating these results in vivo employing shRNA to generate a stable knockdown of c-Jun in pancreatic cancer cells (MIA PaCa-2).
Citation Format: Anjali V. Sheahan, Levon M. Khachigian. c-Jun as a target in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3121. doi:10.1158/1538-7445.AM2013-3121
Abstract 3123: The Notch pathway inhibits TGF-β signaling in breast cancer through HEYL-mediated crosstalk.
Authors: Liangfeng Han , Diehl Adam , Nguyen Nguyen K. , Korangath Preethi , Weiwen Teo , Zhang Zhe , Kominsky Scott , Argani Pedram , Landberg Goran , Sukumar Saraswati V. 
Published: August 2014

Abstract
Acquired resistance to Transforming growth factor-β (TGF-β) is a key step in the early stages of tumorigenesis. Mutations of TGF-β signaling components, often found in other cancers, are rare in breast cancer, and little is known about the development of this resistance in breast cancer. On the other hand, activation of Notch pathway is known to play a substantial role in promoting breast cancer development. We hypothesized that crosstalk between these two pathways occurs through HEYL, a basic helix-loop-helix (bHLH) transcription factor, and a known direct target of Notch. We found that HEYL is overexpressed in 40% of breast cancers. Expression of Notch increased HEYL expression while knockdown of RBP-J, a critical mediator of Notch, reduced HEYL expression in HS578T and MDAMB-231 breast cancer cells. Taking into account the contradictory biological effects of Notch and TGF-β signaling, we sought to examine whether HEYL inhibits the TGF-β pathway. TGF-β treatment or Smad3 overexpression significantly increased the luciferase activity of the TGF-β responsive reporter vector, p3TP-Luc, and the P15 (CDKN2B) gene promoter, but this transactivation was strongly inhibited by HEYL. Bimolecular fluorescence complementation assays confirmed the interaction between Smad 3 and HEYL; immunoprecipitation assays with deletion constructs showed that the Basic domain of HEYL interacts with the MH2 domain of Smad3, and that their interaction is necessary for HEYL to inhibit TGF-β signaling. In addition, using a tet-off inducible breast cancer cell model, HEYL was shown to transcriptionally up-regulate many genes that drive metastasis and tumor angiogenesis. Supporting this concept, HEYL/HER2 double transgenic mice showed nearly 50% increase in lung metastasis (20% vs 46%) compared to HER2/neu mice. Similarly, lung colonization occurred in 100% of mice injected with MDAMB231 while HEYL-shRNAs reduced incidence to 50%. Therefore, HEYL promotes breast cancer growth and metastasis in Smad-dependent and Smad-independent mechanisms.
Citation Format: Han Liangfeng, Adam Diehl, Nguyen K. Nguyen, Preethi Korangath, Teo Weiwen, Zhe Zhang, Scott Kominsky, Pedram Argani, Goran Landberg, Saraswati V. Sukumar. The Notch pathway inhibits TGF-β signaling in breast cancer through HEYL-mediated crosstalk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3123. doi:10.1158/1538-7445.AM2013-3123
Abstract 3125: KAP1 promotes malignant properties of breast cancer cells and regulates the expression of multiple KRAB-ZNFs.
Authors: Addison Joseph B. , Galeeva Renata , Chen Dongquan , Pugacheva Elena N. , Ivanov Alexey V. 
Published: August 2014

Abstract
Background and Objective: Chromatin remodeling is fundamental for normal development and is universally affected in cancer cells. The largest family of human transcription factors, KRAB-ZNF repressors, and their essential cofactor KAP1 play important roles in chromatin organization and regulate multiple cellular processes such as cell differentiation, pluripotency, apoptosis, DNA repair and imprinting. Here, we explored the role of KAP1 and KRAB-ZNFs in breast cancer.
Methods: Using cancer patient samples, in vitro and animal xenograft model we analyzed KAP1 role in cancer cell proliferation and primary tumor formation.
Results: Patient sample analysis showed KAP1 and KRAB-ZNFs overexpression in significant proportion of breast tumors. KAP1 depletion in a panel of breast cancer cell lines inhibited cancer cell proliferation, while KAP1 overexpression stimulated cell growth. Concordantly, KAP1 knockdown in MDA-MB-231LN human breast cancer cells inhibited primary tumor growth in orthotopic xenograft mouse model, while KAP1 overexpression had an opposite, growth stimulatory effect. KAP1 depletion resulted in decreased expression of a number of cancer-associated genes. Functional in vitro studies provided evidence that KAP1 positively regulates expression of multiple KRAB-ZNFs.
Discussion and Conclusions: These results thus establish KAP1 as an oncogenic factor in breast cancer. Grant support: NIH NCRR grant P20 RR16440 and Susan G. Komen for the Cure grant KG110350.
Citation Format: Joseph B. Addison, Renata Galeeva, Dongquan Chen, Elena N. Pugacheva, Alexey V. Ivanov. KAP1 promotes malignant properties of breast cancer cells and regulates the expression of multiple KRAB-ZNFs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3125. doi:10.1158/1538-7445.AM2013-3125
Abstract 3126: Insulinoma-associated 1 is a key transcriptional regulator of growth and survival-promoting pathways in small cell lung cancer.
Authors: Christensen Camilla L. , Shimamura Takeshi , Akbay Esra A. , Michaelsen Signe R. , Poulsen Hans S. , Wong Kwok-kin 
Published: August 2014

Abstract
Insulinoma-associated 1 (INSM1) is neuroendocrine (NE) transcription factor which temporal and spatial expression pattern is restricted to regions undergoing NE differentiation during embryogenesis. INSM1 is however re-expressed at high levels in small-cell lung cancer (SCLC) together with an array of other NE markers. The NE signature of SCLC is a central diagnostic tool for the disease but recent data pinpoints that this distinct signature might play a role in SCLC pathogenesis.
The functional role of INSM1 in SCLC was here investigated by shRNA-mediated silencing of INSM1 in a panel of SCLC cell lines. Upon silencing of INSM1, significant reduction in cell viability was observed as measured by MTT assay. This reduction in cell viability was concomitant with decreased cell proliferation and increased apoptosis as measured by BrdU incorporation and cleaved caspase 3/7 levels, respectively. Accordingly with phenotypic growth changes it was demonstrated that INSM1 silencing caused reduced phosphorylation of members of the growth- and survival-promoting PI3K/Akt, MAPK and JAK-STAT signaling pathways and reduced levels of the inhibitors of apoptosis proteins (IAPs) members c-IAP1, XIAP and survivin. Importantly, it was shown that INSM1 is an upstream regulator of signatures previously shown to play a role in SCLC tumorigenesis, including achate-scute homolog 1 (ASCL1) and Sonic Hedgehog (SHh) pathway. Upon silencing of INSM1, a decrease in mRNA and protein levels of ASCL1 and downstream targets aldehyde dehydrogenase 1 (ALDH1) and delta-like ligand 3 (DLL3) was observed. Furthermore, mRNA levels of the SHh positive mediators Gli2, Gli3 and Smoothened was downregulated while the SHh inhibitor Patched was upregulated upon INSM1 silencing. Futhermore, overexpression of the Notch1 intracellular domain in SCLC cells resulted in a significant reduction in INSM1 expression and cell viability. This suggest that a master inhibitor of the NE signature, Notch1 signaling, could be an inhibitor of INSM1-driven tumorigenesis.
In conclusion, INSM1 is a potential key driver of growth- and survival-promoting pathways in SCLC and warrants further investigation of INSM1 as a therapeutic target.
Citation Format: Camilla L. Christensen, Takeshi Shimamura, Esra A. Akbay, Signe R. Michaelsen, Hans S. Poulsen, Kwok-kin Wong. Insulinoma-associated 1 is a key transcriptional regulator of growth and survival-promoting pathways in small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3126. doi:10.1158/1538-7445.AM2013-3126