bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3607: Metastasis-associated protein 1 negatively regulates expression of androgen receptor in ER-positive breast cancer cells
Authors: Kim SeungSu 
Published: July 2017

Abstract
Androgen receptor (AR) is expressed in more than 80% of ER-positive breast cancer and its expression is correlated with better prognosis in ER-positive breast cancer. However, little is known about the regulation of AR expression in breast cancer. We have previously reported that metastasis-associated protein 1 (MTA1), a cancer-promoting gene that is overexpressed in breast cancer, increases the expression of ERα in breast cancer. Here, we investigated the role of MTA1 on AR expression in three different ER-positive breast cancer cell lines. First, small interfering RNA-mediated knockdown of MTA1 increased protein and mRNA expression of AR in MCF7, T47D, and ZR75-1. Overexpression of MTA1 down-regulated expression of AR in these cell lines. Activity of the reporter-encoding AR promoter (-2408 bp ~ +1126 bp) was decreased in the presence of MTA1 in a dose-dependent manner. Analysis of the chromatin immunoprecipitation sequencing data (http://encodeproject.org/ENCODE) revealed that MTA1 may bind to 1 kilo base downstream of AR transcription start site. Together, our results demonstrated that MTA1 negatively regulates expression of AR in breast cancer cells. These results suggest that the negative regulation of AR may be associated with the cancer promoting effects of MTA1, which may provide a therapeutic opportunity against ER-positive breast cancer.
Citation Format: SeungSu Kim. Metastasis-associated protein 1 negatively regulates expression of androgen receptor in ER-positive breast cancer cells [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 3607. doi:10.1158/1538-7445.AM2017-3607
Abstract 3614: Antibody validation revises estrogen receptor beta research
Authors: Andersson Sandra , Sundberg Mårten , Pristovsek Nusa , Ibrahim Ahmed , Jonsson Philip , Katona Borbala , Clausson Carl-Magnus , Zieba Agata , Ramström Margareta , Söderberg Ola , Williams Cecilia , Asplund Anna 
Published: July 2017

Abstract
The discovery of estrogen receptor β (ERβ/ESR2) in 1996 was a landmark discovery. Its homology with breast cancer pharmacological target and predictive biomarker estrogen receptor α (ERα /ESR1) raised hopes for improved endocrine therapies. However, after twenty years of intense research the therapeutic promises have not materialized. We here perform a rigorous validation of 13 anti-ERβ antibodies, and demonstrate that the vast majority are unspecific. Using well-characterized controls and a panel of validation methods, we conclude that only the rarely used monoclonal antibody PPZ0506 targets ERβ in a specific manner in immunohistochemistry. We applied this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, and found that detection of ERβ protein is limited to testis, ovary, placenta, lymphoid cells, granulosa cell tumors, and a subset of malignant melanoma and thyroid cancers. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. We did not find evidence that normal or cancerous human breast express ERβ protein. Our study highlights how inadequately validated antibodies can lead an exciting and promising field astray.
Citation Format: Sandra Andersson, Mårten Sundberg, Nusa Pristovsek, Ahmed Ibrahim, Philip Jonsson, Borbala Katona, Carl-Magnus Clausson, Agata Zieba, Margareta Ramström, Ola Söderberg, Cecilia Williams, Anna Asplund. Antibody validation revises estrogen receptor beta research [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 3614. doi:10.1158/1538-7445.AM2017-3614
Abstract 3619: Role of MTDH in estrogen-regulated gene expression
Authors: Meng Xiangbing , Li Yujun , Bosquet Jesus Gonzalez , yang shujie , Thiel Kristina W. , Leslie Kimberly K. 
Published: July 2017

Abstract
Disruption of estrogen signaling is widely associated with the development of breast, endometrial, and ovarian cancers. As a multifunctional mediator of carcinogenesis, metadherin (MTDH)/AEG-1 overexpression has been associated with numerous types of cancers, with reported roles in tumor initiation, proliferation, invasion, metastasis and chemoresistance. At the molecular level, MTDH has been shown to interact with proteins that drive tumorigenesis, including NF-κB, PLZF, BCCIPα and SND1. Through analysis of the Cancer Genome Atlas (TCGA) datasets for ER-positive endometrial and breast cancers, we found that over 25% of all gene expression correlated with MTDH. Using Affymetrix microarrays, we characterized the differences in gene expression between estrogen-treated parental and MTDH-deficient endometrial and breast cancer cells. We also explored a possible interaction between MTDH and ER by immunoprecipitation and found that MTDH and ER associated in both breast and endometrial cancer cells in response to estrogen. Reciprocal co-immunoprecipitation analysis demonstrated that acute estrogen stimulation promoted the interaction of MTDH with ER in the nucleus. These data suggest that MTDH and ERα interact in the nucleus with estrogen treatment, and MTDH/ER co-regulated genes may have functions in drug resistance, metastasis and tumor progression.
Citation Format: Xiangbing Meng, Yujun Li, Jesus Gonzalez Bosquet, shujie yang, Kristina W. Thiel, Kimberly K. Leslie. Role of MTDH in estrogen-regulated gene expression [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 3619. doi:10.1158/1538-7445.AM2017-3619
Abstract 3627: Validation of PPARG and RXRA as drivers of bladder cancer
Authors: Goldstein Jonathan T. , Strathdee Craig , Duke Fujiko , Shih Juliann , Meyerson Matthew 
Published: July 2017

Abstract
A subset of muscle-invasive bladder cancer (BLCA) is typified by PPARG pathway activation. PPARG focal gene amplification occurs in 15% of bladder cancer patients, and similarly, 5% of BLCA patients possess hotspot mutations in the requisite heterodimer partner of PPARG, RXRA (S427F, S427Y). We used genetic perturbation to study the role of PPARG in bladder cancer. Our results show that overexpression of RXRA and PPARG mutant alleles activate expression of PPARG and PPARA target genes in a ligand-independent manner, and that bladder cancer cell lines are dependent on PPARG for viability. These findings suggest that PPARG may be a promising therapeutic target for treatment of bladder cancer.
Citation Format: Jonathan T. Goldstein, Craig Strathdee, Fujiko Duke, Juliann Shih, Matthew Meyerson. Validation of PPARG and RXRA as drivers of bladder 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 3627. doi:10.1158/1538-7445.AM2017-3627
Abstract 365: Cross-talk between BRAF and Hippo/YAP1 signaling in melanoma
Authors: Raj Mohan Kumar Durai , Nguyen Jonathan , Bora-singhal Namrata , Messina Jane , Gibney Geoffrey , Chellappan Srikumar 
Published: July 2017

Abstract
Hippo/YAP1 signaling pathway is a tumor suppressive pathway that controls the organ size by modulating the cell growth, proliferation and apoptosis and is conserved from Drosophila to mammals. In mammals, the Hippo tumor suppressor pathway consists of cascade of kinases in which MST1/2 phosphorylates and activates LATS1/2. The latter phosphorylates the oncogenic transcriptional coactivators YAP1 and TAZ, leading to their cytoplasmic retention by 14-3-3 proteins and/or degradation. Inactivation of MST and LATS kinases allows YAP1 and/ or TAZ nuclear translocation and subsequent activation of their target genes.
Deregulation of Hippo pathway can induce tumors in model organisms and occurs in wide range of human cancers including melanoma. Merlin, a key component of this pathway which inhibits YAP1, is mutated/deleted in 8% of melanoma. Majority of uveal melanomas are driven by Gq/11 mutations that trigger YAP1 nuclear translocation, promoting tumor growth. High levels of YAP1 in BRAFV600E mutant tumors confer resistance to RAF- and MEK- targeted therapy in patients.
Our results show that YAP1 level is elevated in melanoma and the YAP1 inhibitor verteporfin alone or in combination with B-RAF inhibitor PLX4720 reduces the viability, invasion and anchorage-independent growth of B-RAF V600E mutant SK-MEL-28 and SK-MEL-5 cells. In addition, verteporfin treatment also reduced the viability of PLX4720 resistant 1205 cells. Western blot analysis of verteporfin and PLX4720 treated SK-MEL-28 and SK-MEL-5 cells displayed reduced levels of YAP1, B-RAF, pERK, MEK and pMEK.
We also report a novel physical interaction between YAP1 and B-RAF; this could be detected using double immunofluorescence and immunoprecipitation-western blotting techniques in both B-RAF V600E mutant and N-Ras mutant melanoma cells. Proximity ligation assays on tissue microarray showed that YAP1-B-RAF interaction is elevated in metastatic melanoma compared to normal skin. These novel findings highlight the crosstalk between B-RAF and Hippo/YAP1 signaling which might have a
potential role in melanoma development and progression. Further, experiments are in progress to elucidate the functional significance of YAP1-B-RAF interaction in melanoma.
Citation Format: Mohan Kumar Durai Raj, Jonathan Nguyen, Namrata Bora-singhal, Jane Messina, Geoffrey Gibney, Srikumar Chellappan. Cross-talk between BRAF and Hippo/YAP1 signaling in melanoma [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 365. doi:10.1158/1538-7445.AM2017-365
Abstract 3668: Oncolytic adenoviruses expressing OX40L or GITRL immune modulators show antitumor effect on immune-competent mouse breast cancer models
Authors: Martinez Francisco W. Puerta , Rivera Yisel A. , Nguyen Teresa , Fan Xuejun , Henderson Jared M. , Rehnuma Shifat , Hossain Mohammad B. , Jiang Hong , Fueyo Juan , Manzano Candelaria Gomez 
Published: July 2017

Abstract
Metastasis of advanced stage cancers remains as the main cause of morbidity and mortality in oncologic patients. Metastatic cancers, especially those that metastasize to the brain, are generally resistant to conventional therapies. Thus, more innovative and efficacious therapies are urgently needed. Therapeutic goals are the specific targeting of malignant cells, shrinkage of stablished tumors, prevention and/or eradication of metastases and, ultimately, induction of a specific anti-tumor immune response. In this study we tested the efficiency of a treatment regimen consisting of oncolytic adenoviruses combined with specific immune regulators to prevent tumor progression and metastasis. In order to do so, mouse metastatic breast cancer cells 4T1 or 66c14, were orthotopically implanted in female BALB/c mice. The resulting primary tumors were treated with multiple doses of third generation adenoviruses targeting different immune checkpoints, such as, OX40/OX40L and GITR/GITRL pathways in the immune synapse. The treatment with these adenoviral constructs resulted in T cells activation and reduction of the metastases in 50% of the mice. In addition, the size and number of the metastases detected in lungs were significantly lower comparing with those observed in the control groups. Survival rates were also significantly different (P &lt; 0.046) when compared to controls. FACS analysis of isolated tumor-infiltrating lymphocytes, as well as, splenocytes showed that OX40/OX40L or GITR/GITRL immune therapies were able to activate and increase the number of cytotoxic T cells and suppress tumor anergy. In summary, we demonstrated for the first time that Delta-24-RGDOX and Delta-24-GREAT, expressing OX40L and GITRL respectively, display antitumor effect on immune competent models of metastatic breast cancer.
Citation Format: Francisco W. Puerta Martinez, Yisel A. Rivera, Teresa Nguyen, Xuejun Fan, Jared M. Henderson, Shifat Rehnuma, Mohammad B. Hossain, Hong Jiang, Juan Fueyo, Candelaria Gomez Manzano. Oncolytic adenoviruses expressing OX40L or GITRL immune modulators show antitumor effect on immune-competent mouse 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 3668. doi:10.1158/1538-7445.AM2017-3668
Abstract 3711: R-Ras is required for T cell trafficking in high endothelial venues and implicated in anti-tumor immunity
Authors: Chan Andrew M. , Yan Xiaocai , Liu Wai Nam , Yan Mingfei 
Published: July 2017

Abstract
R-Ras belongs the RAS superfamily of small GTP-binding proteins implicated in cell adhesion signaling. Unlike classical Ras proteins, R-Ras is not activated by growth factor receptors. Rather, its GTPase activity is modulated by molecules implicated in cell-cell adhesion including semaphorins and notch. Using an R-Ras knockout mouse strain, we have previously reported that R-Ras is required for murine Dendritic cell functions. Further characterization of this mouse strain revealed reduced cellularity of peripheral lymph nodes (PLNs) by 40% with T cell regions in the paracortex in which high endothelial venules (HEV) resided were less prominent when compared with wild-type (WT) mice. Consistently, immunohistological analysis for MECA-79, a marker of mature HEV, showed a 3- to 4-fold decrease in staining intensity. This is correlated with a 30-40% reduction in the number of CD62L+ CD4 and CD8 T cells in PLNs. Furthermore, R-Ras null T cells had reduced proliferative and homing capacity when compared with WT. More importantly, we demonstrated for the first time that the chemokine CCL21 was able to stimulate the GTP-loading of R-Ras within 15 seconds of addition. Indeed, R-Ras null T-cells displayed reduced binding to soluble ICAM-1 as well as to 2H-11 endothelial cells. To explore the role of R-Ras in anti-tumor immunity, B16/F10 melanoma cells were injected subcutaneously to WT and R-Ras null mice. In addition, a mouse breast tumor model was generated ineither WT or R-Ras-null genetic background. Tumor development and the number of infiltrating immune cells were analyzed to examine if R-Ras was involved in either anti- or pro-tumor immune responses. This work was supported by NIH CA78509 (AMC), MH59771 (AMC). MY was supported by Hong Kong PhD Fellowship Scheme (PF12-13584) and AMC was supported by the Lo Kwee-Seong Seed Fund, and a General Research Fund Grant, 14120915, from Hong Kong University Grants Committee.
Note: This abstract was not presented at the meeting.
Citation Format: Andrew M. Chan, Xiaocai Yan, Wai Nam Liu, Mingfei Yan. R-Ras is required for T cell trafficking in high endothelial venues and implicated in anti-tumor immunity [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 3711. doi:10.1158/1538-7445.AM2017-3711
Abstract 3719: Bicyclic peptides for PET imaging of MT1-MMP expressing tumors
Authors: Teufel Daniel , Harrison Helen , Campbell Spencer , Stace Catherine , Walker Edward , Lutz Robert J. , Park Peter , Eder Matthias , Bauder-Wüst Ulrike , Schierbaum Ursula , Leotta Karin , Kopka Klaus , Haberkorn Uwe 
Published: July 2017

Abstract
The Bicycle® technology is based on repertoires of short peptides displayed on the surface of bacteriophages which can be modified with homo-trifunctional organochemical scaffolds, thus creating large diverse libraries of constrained, bicyclic peptides. These large combinatorial libraries have been extensively used for iterative selections to identify high affinity binding peptides to a wide array of targets, including receptors, interleukins and proteases.
Bicyclic peptides are chemically synthesized macrocyclic entities with drug-like properties that exhibit sub-nanomolar affinities and exquisite selectivity towards targets. Unlike biologics, their synthetic nature allows facile modulation of metabolic and pharmacokinetic properties, as well as site-specific conjugation to effector molecules such as fluorophores, radionuclides, and cytotoxic drugs.
In the present work, novel phage display derived bicyclic peptides were identified targeting the matrix metalloproteinase 14 (also known as MT1-MMP), a tumor associated surface protein overexpressed in a variety of cancers (i.e. lung, breast). A prototype bicyclic peptide with high affinity to MT1-MMP (Kd at ~1 nM) was identified, and confocal microscopy using fluoresceinated bicyclic peptide derivatives shows target-dependent internalisation in MT1-MMP+ cells. In the in vivo mouse, selective tumor binding in an MT1-MMP+ xenograft model is demonstrated for a DOTA conjugate loaded with Ga-68 or Lu-177. Upon proteolytic optimization of the prototype bicycle peptide, a striking enhancement in tumor signal is observed in biodistribution studies. Compared to radiolabeled antibodies directed against the same target, the lead compound showed fast background clearance (&lt; 1 %ID/g for all organs apart from kidneys) resulting in high imaging contrast in µPET studies as early as 30 minutes post injection. Importantly, most of the non-tumor associated bicyclic peptide rapidly clears into the bladder.
Together, tumor targeting bicyclic peptides can, through their small size and high selectivity, facilitate efficient penetration and visualization of tumors in vivo, demonstrating their potential as diagnostic imaging agents in profiling and therapeutic management of patients.
Citation Format: Daniel Teufel, Helen Harrison, Spencer Campbell, Catherine Stace, Edward Walker, Robert J. Lutz, Peter Park, Matthias Eder, Ulrike Bauder-Wüst, Ursula Schierbaum, Karin Leotta, Klaus Kopka, Uwe Haberkorn. Bicyclic peptides for PET imaging of MT1-MMP expressing tumors [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 3719. doi:10.1158/1538-7445.AM2017-3719
Abstract 3728: Imaging biomarkers of aromatase-inhibitor induced joint pain
Authors: Goldstein Brian A. , Taljanovic Mihra , Chalasani Pavani , Kwoh C. Kent , Hadden Amanda , Witte Russell , Martinez Jessica 
Published: July 2017

Abstract
Estrogen receptor positive (ER+) breast cancer patients undergoing treatment with aromatase inhibitors (AI) tend to discontinue the supplement when to painful side effects appear. It is believed that women with AI-induced musculoskeletal syndrome (AIMSS) have specific physiological conditions that differentiate them from women with normal aging-related inflammatory processes (e.g., rheumatoid arthritis or RA). Ultrasound shear wave elastography (USWE) provides a real-time, quantitative assessment of the elastic modulus of soft tissue, which is a potential biomarker that is altered in women with AIMSS.
Because USWE is a completely noninvasive technique available on state-of-the-art clinical ultrasound scanners, it can be readily applied to study patients who undergo AI treatment and help predict adverse effects during therapy.
A Siemens s3000 clinical scanner and 9 MHz linear probe were used for USWE of the hands and wrists in postmenopausal women on AI, postmenopausal women with RA and healthy postmenopausal women. The scans included an evaluation of major wrist tendons, nerve, and joints with shear wave velocities ranging from 0.5 to 15 m/s, which are directly related to the local shear modulus – an absolute measure of tissue stiffness. The ultrasound images and raw shear wave data were then analyzed in MATLAB-TM using a custom graphical user interface (GUI) to calculate the distribution of velocities (or shear moduli) in a user-defined region of interest (ROI). The results were exported to a spreadsheet in Excel for further analysis and comparison among the different groups.
Initial results suggest the shear wave velocity and estimated Young’s modulus (λ) were significantly higher in AI patients (14.6 ± 0.2 m/s, λ=642 ± 17 kPa) compared to RA (6.84 ± 1.1 m/s, λ=143 ± 43 kPa) and healthy (7.58 ± 0.9 m/s, λ=174 ± 42 kPa) patients. These values suggest that the mechanical properties of tendons in the wrist may change during treatment with AI and contribute to joint pain in these subjects. It is critical that ER+ patients on AI complete their full treatment. As a potential biomarker of AIMSS and associated pain, USWE may help predict which patients are most susceptible to these side effects, promote early intervention to reduce or eliminate symptoms, and help increase adherence to AI therapy.
Citation Format: Brian A. Goldstein, Mihra Taljanovic, Pavani Chalasani, C. Kent Kwoh, Amanda Hadden, Russell Witte, Jessica Martinez. Imaging biomarkers of aromatase-inhibitor induced joint pain [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 3728. doi:10.1158/1538-7445.AM2017-3728
Abstract 373: Wnt signaling induces anti-apoptotic effect in colorectal cancer cells through the suppression of IFITs
Authors: Ohsugi Tomoyuki , Yamaguchi Kiyoshi , Zhu Chi , Ikenoue Tsuneo , Furukawa Yoichi 
Published: July 2017

Abstract
Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through the activation of β-catenin/TCF complex. Although genes up-regulated by Wnt/β-catenin signaling has been well studied, the down-regulated genes are poorly understood. To clarify the comprehensive changes regulated by the signaling in colorectal cancer cells, we explored a global gene expression of CRC cells transfected with β-catenin siRNAs or dominant negative form of TCF7L2 (dnTCF7L2). Consequently, a set of genes that were negatively regulated by β-catenin/TCF were identified. Among the genes, three members of interferon-induced proteins with tetratricopeptide repeats (IFIT) family (IFIT1, IFIT2, and IFIT3) expression were significantly increased by the inhibition of β-catenin/TCF. Comparison of gene expression data from normal colonic mucosa and the tumor tissues showed that the expression of IFIT1 and IFIT2 in the tumors was significantly lower than that in normal tissues. To elucidate the mechanism of IFITs expression regulated by β-catenin/TCF, we performed a reporter assay using plasmid containing 1.2-kb of 5’-flanking region of the IFIT2 gene. As a result, the reporter activity was significantly enhanced by either transduction of β-catenin or dnTCF7L2, suggesting that blockage of β-catenin/TCF stimulated IFITs through the promoter. In addition, we found that overexpression of IFIT2 increased apoptosis and decreased cell proliferation in SW480 and HCT116 cells. These results imply that Wnt signaling may promote anti-apoptotic effect in cancer cells through the suppression of IFIT2. Our findings suggest that analysis of down-regulated genes in response to activated Wnt/β-catenin signaling provides a better understanding of human colorectal carcinogenesis.
Citation Format: Tomoyuki Ohsugi, Kiyoshi Yamaguchi, Chi Zhu, Tsuneo Ikenoue, Yoichi Furukawa. Wnt signaling induces anti-apoptotic effect in colorectal cancer cells through the suppression of IFITs [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 373. doi:10.1158/1538-7445.AM2017-373