bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2975: Collagen type XI alpha 1 confers cisplatin chemoresistance in ovarian cancer through inhibitor of apoptosis proteins (IAPs)
Authors: Rada Miran , Cha Jennifer , Sage Jessica , Orsulic Sandra , Cheon Dong-Joo 
Published: July 2017

Abstract
Ovarian cancer is the most lethal gynecological cancer, which affects one in 70 females in the United States during their lifetime. While cisplatin is the frontline treatment for ovarian cancer, chemoresistance severely limits the treatment success. The goal of this study is to identify novel therapeutic targets to overcome cisplatin resistance. We recently identified Collagen type XI alpha 1 (COL11A1) as a novel biomarker associated with cisplatin resistance in ovarian cancer. COL11A1 is a component of the tumor stroma and its expression is restricted to cancer-associated fibroblasts (CAFs) adjacent to tumor cells. We further showed that COL11A1 protects ovarian cancer cells from cisplatin-induced apoptosis, yet the underlying mechanism is largely unknown. To understand the molecular mechanism by which COL11A1 protects cancer cells from cisplatin-induced apoptosis, we overexpressed COL11A1 in ovarian cancer cells and performed RNA-Seq. Our RNA-Seq data revealed that COL11A1 did not change the levels of genes involved in cisplatin transport, inactivation, and DNA repair pathways in cancer cells, which are well-established mechanisms to confer cisplatin resistance. Rather, COL11A1 enhances the expression of the Inhibitors of Apoptosis Proteins (IAPs), including XIAP, BIRC2 (c-IAP1) and BIRC3 (c-IAP2). Using a full-length COL11A1 protein, genetic manipulation, and co-culture method, we confirmed that COL11A1 significantly increases the expression of IAPs upon cisplatin treatment. The inhibition of XIAP, BIRC2 and BIRC3 with an IAP antagonist BV6 attenuated the ability of COL11A1 to inhibit cisplatin-mediated apoptosis. Our data indicates that COL11A1 activates Akt, and Akt is known to phosphorylate XIAP at serine-87, which protects it from ubiquitination and degradation in response to cisplatin. Collectively, our data identify IAP as a mediator of COL11A1’s action in blocking cisplatin-induced apoptosis.
Note: This abstract was not presented at the meeting.
Citation Format: Miran Rada, Jennifer Cha, Jessica Sage, Sandra Orsulic, Dong-Joo Cheon. Collagen type XI alpha 1 confers cisplatin chemoresistance in ovarian cancer through inhibitor of apoptosis proteins (IAPs) [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 2975. doi:10.1158/1538-7445.AM2017-2975
Abstract 2983: Tumor induced stromal STAT1 deregulates mammary tissue homeostasis and accelerates breast cancer
Authors: Zellmer Victoria R. , Schnepp Patricia M. , Fracci Sarah L. , Tan Xuejuan , Howe Erin N. , Zhang Siyuan 
Published: July 2017

Abstract
The tumor microenvironment (TME) – the dynamic tissue space in which the tumor exists – plays a significant role in tumor initiation and is a key contributor in cancer progression. Little is known about the tumor-induced changes in the adjacent tissue stroma. Herein, we sought to explore tumor-induced changes in the TME at the morphological and molecular level to further characterize cancer progression. We show that tumor-adjacent mammary glands (TAGs) display altered branch morphology, increased expression of αSMA particularly in myofibroblasts, and an increased capacity to form mammospheres in 2D suspension culture. FACS analysis showed that TAGs contain an increased number of Lin-CD24+/CD49+ enriched mammary gland stem cell (MaSCs) population, suggesting deregulated tissue homeostasis in TAGs. We conducted comparative transcriptomics on TAGs and contralateral control glands. Meta-analysis on differentially expressed genes from our RNA-seq dataset plus two breast cancer stromal patient microarray datasets identified shared upregulation of STAT1, which we verified in tumor-adjacent tissues. Knockdown of STAT1 in caveolin-deficient mouse embryonic fibroblasts (CAFs) cocultured with human breast cancer cells altered cancer cell proliferation, further suggesting the role of STAT1 as a stromal contributor of tumorigenesis. Furthermore, in our proof-of-concept in vivo experiment, co-treatment with fludarabine, a FDA-approved STAT1 activation inhibitor and DNA synthesis inhibitor, in combination with doxorubicin, showed enhanced therapeutic efficacy in treating mouse mammary gland tumors. Our results demonstrate that stromal STAT1 expression could promote tumor progression and is a potential therapeutic target for breast cancer.
Citation Format: Victoria R. Zellmer, Patricia M. Schnepp, Sarah L. Fracci, Xuejuan Tan, Erin N. Howe, Siyuan Zhang. Tumor induced stromal STAT1 deregulates mammary tissue homeostasis and accelerates 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 2983. doi:10.1158/1538-7445.AM2017-2983
Abstract 2984: The chemokine CCL2/CCR2 signaling mediated fibroblasts-cancer cells crosstalk promotes basal like breast cancer progression
Authors: Yao Min , Fang Wei Bin , Fan Fang , Alvarez Nehemiah , Fields Patrick E. , Cheng Nikki 
Published: July 2017

Abstract
Cancer associated fibroblasts are the most abundant stromal cells in breast cancer, but their function in cancer progression has not been fully understood. We previously identified that the chemokine CCL2 was highly expressed in breast cancer associated fibroblasts, and high stromal CCl2 expression predicted poor outcome in basal like breast cancer. CCL2 is known to recruit monocyte/macrophage and promotes cancer progression. We previously found that recombinant CCL2 can directly signal to breast cancer cells and promote cell survival and invasion in vitro. In this study, we aimed to determine the functional importance of CCL2 signaling mediated fibroblast-cancer cell interactions in breast cancer progression. We used a fibroblast and cancer cell co-graft mouse model as the main functional assay. We generated primary fibroblasts from mouse mammary tumor and human breast cancer, and confirmed most of they expressed high level of CCL2. When co-grafted with the human basal breast cancer cell line MCF10A-CA1D into nude mice, fibroblasts enhanced xenograft growth. Stable knockdown of CCL2 expression from fibroblasts significantly reduced its ability in tumor growth promotion, while knockdown CCL2 from cancer cells did not. Decreased CCL2 production from fibroblasts resulted in increased apoptosis and autophagy in tumor samples. To determine the importance of direct CCL2 signaling to cancer cell, we generated the CCL2 receptor CCR2 mutant CA1D cancer cell lines by CRISPR-Cas9 targeting technology. Mutation of CCR2 in cancer cell significantly reduced tumor growth when co-grafted with CCL2 secreting fibroblasts. Lastly, we tested continuous delivery of CCL2 neutralizing antibody in the co-graft tumor model, but observed minimal therapeutic effect. Further examination of blood CCL2 level revealed an increased production of CCL2 from fibroblasts and mouse host after antibody treatment, which may contribute to the lack of therapeutic effect. In summary, our studies demonstrated the importance of CCL2/CCR2 signaling mediated fibroblasts-cancer cell interaction in basal like breast cancer progression. The CCL2 signaling pathway can be potentially served as therapeutic target, but requires development of efficient targeting strategy.
Citation Format: Min Yao, Wei Bin Fang, Fang Fan, Nehemiah Alvarez, Patrick E. Fields, Nikki Cheng. The chemokine CCL2/CCR2 signaling mediated fibroblasts-cancer cells crosstalk promotes basal like breast cancer progression [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 2984. doi:10.1158/1538-7445.AM2017-2984
Abstract 2989: Expression of immune checkpoints proteins and their prognostic relevance in prostate cancer
Authors: Hube-Magg Claudia , Schroeder Cornelia , Simon Ronald , Kluth Martina , Krech Till , Büscheck Franziska , Jacobsen Frank , Höflmayer Doris , Budäus Lars , Huland Hartwig , Graefen Markus , Sauter Guido , Schlomm Thorsten 
Published: July 2017

Abstract
Immune checkpoint proteins including programmed death ligand 1, 2 (PD-L1, PD-L2) and B7-H3 play important roles for immune evasion in many cancer types. PD-L1 is an established therapeutic target in lung cancer and in a growing number of other indications. The clinical success of PD-L1 inhibitors has accelerated the development of drugs also targeting PD-L2 and B7-H3. In prostate cancer, studies on the prevalence and clinical relevance of these proteins have been inconclusive. Here, we performed immunohistochemical analysis of PD-L1, PD-L2 and B7-H3 in our large prostate cancer prognosis tissue microarray (TMA) containing tissue samples from more than 17,000 patients. Normal prostate glands were negative for PD-L1 and B7-H3, but positive for PD-L2. We found that 47% of 12,808 interpretable cancers showed B7-H3 expression, and 92% of 9,463 cancers showed PD-L2 expression, while expression of PD-L1 was virtually absent (0.2% of 17,392 tumors) in epithelial cells. Stroma cells and immune cells were entirely negative for PD-L1 and B7-H3, while some faint staining of lymphocytes was occasionally observed for PD-L2. In cancers, PD-L2 and B7-H3 staining had different prognostic impact, which depended on the ERG status: B7-H3 expression was linked to young patient age, advanced stage, high Gleason grade, lymph node metastasis (p&lt;0.0001 each), presence of PTEN deletion (p&lt;0.0001), and poor prognosis in ERG negative cancers (p&lt;0.0001), while PD-L2 expression was linked to beneficial tumor features and good prognosis exclusively in tumors with ERG fusion (p&lt;0.0001). In a multivariate analysis including pT stage, Gleason grade, nodal stage, resection margin and preoperative PSA level, B7-H3 expression was an independent prognostic factor (p=0.0004). In summary, the results of our study identify a subset of young patients with ERG negative aggressive prostate cancers that might benefit from anti-B7-H3 therapy in the future. PD-L2 expression appears to protect tumors from progression and does not seem to be suitable as a potential target in prostate cancer. PD-L1 expression is extremely rare in this disease, suggesting that only few prostate cancer patients might benefit from PD-L1 inhibitors.
Citation Format: Claudia Hube-Magg, Cornelia Schroeder, Ronald Simon, Martina Kluth, Till Krech, Franziska Büscheck, Frank Jacobsen, Doris Höflmayer, Lars Budäus, Hartwig Huland, Markus Graefen, Guido Sauter, Thorsten Schlomm. Expression of immune checkpoints proteins and their prognostic relevance in prostate 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 2989. doi:10.1158/1538-7445.AM2017-2989
Abstract 301: Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric cancer
Authors: Hong Jihyung , Sun Der Sheng , Hong Soon Auck , Won Hye Sung , Lee Han Hong , Kim Okran , Ko Yoon Ho 
Published: July 2017

Abstract
Background : Caveolin-1 (Cav-1), as the main component of caveolae, has complex roles in tumourigenesis and clinical outcomes in a variety of human malignancies. We investigated Cav-1 in primary and metastatic tumor of gastric cancer (GC) and its association with clinical outcomes.
Method : All specimens evaluated were obtained from 145 patients with GC who had undergone curative gastrectomy. The primary outcomes measured were the expression levels of Cav-1 by immunohistochemistry and its association with clinicopathologicalparameters and patient survival.
Results : Among the 145 patients, the frequency of high expression of stromal Cav-1 within primary tumor and tumoral Cav-1 protein in metastatic lymph node were 22.5% (18/145) and 16.6% (15/91). In the multivariate analysis tumoral Cav-1 protein in metastatic lymph node showed prognostic significance for relapse-free survival (RFS, HR, 3.934; 95% CI, 1.882-8.224; P&lt;0.001) and cancer-specific survival outcome (CSS, HR, 3.985; 95% CI, 1.620 - 8.623; P = 0.002). In addition, it remained as a strong indicator of poor prognosis for RFS (HR, 3.137; 95% CI, 1.445 - 6.810; P = 0.004) and CSS (HR, 2.509; 95% CI, 1.079 - 5.838; P = 0.033).
Conclusions : High expression of tumoral Cav-1 protein in metastatic lymph node shows a strong negative association with the clinical outcomes in patients with curatively resected GC, suggesting that this protein have potential uses as novel prognostic markers.
Citation Format: Jihyung Hong, Der Sheng Sun, Soon Auck Hong, Hye Sung Won, Han Hong Lee, Okran Kim, Yoon Ho Ko. Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric 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 301. doi:10.1158/1538-7445.AM2017-301
Abstract 3019: The role of TACC3 in the progression from ductal carcinoma in situ to invasive breast cancer
Authors: Campo Loredana , Mathew Maya , breuer Eun-Kyoung , Small William 
Published: July 2017

Abstract
Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer with the potential to become invasive/metastatic. The development of DCIS to invasive breast cancer is an important aspect of breast tumor aggressiveness, however, little is known about the genetic and molecular alterations involved in this progression. Also, analysis of molecular markers and genetic signatures of DCIS and invasive breast cancer have failed to identify transition-specific biomarkers or pathways. Hence, identifying the molecular mechanisms by which DCIS progresses to invasive breast cancer is critical for the success of diagnosis, prognosis and therapy of breast cancer. Members of the transforming acidic coiled-coil (TACC) protein family are key players in the maintenance of centrosome integrity, the regulation of microtubule assembly, and spindle stability during mitosis. TACC3 has been shown to be involved in the regulation of centrosome-microtubule dynamic networks, cell growth and differentiation, and transcription/gene expression through interactions with other molecules. Mounting evidence indicates that high levels of TACC3 may contribute to breast cancer development. Here, we investigated the significance of TACC3 in the transition of DCIS to invasive breast cancer. First, we examined the expression of TACC3 in non-tumorigenic human mammary epithelial MCF10A cells and MCF10DCIS.COM cells, which are known to form DCIS-like lesions in mice and to progress to invasive cancer, and found that the expression of TACC3 is elevated in MCF10DCIS.COM cells compared to MCF10A cells. By analyzing tissue microarray data, we found that expression of TACC3 gradually increased from normal breast to DCIS, and further increased in invasive breast cancer. In addition, ectopic expression of TACC3 in MCF10DCIS.COM cells promoted cell proliferation, migratory and invasive capabilities as well as the epithelial-mesenchymal transition (EMT)-like phenotype. Moreover, MCF10DCIS.COM cells stably expressing TACC3 exhibited increased expression of stemness markers. Interestingly, a small molecule inhibitor of TACC3, KHS101 treatment in MCF10DCIS.COM cells significantly suppressed cell proliferation and the PI3K/AKT signaling pathway while having little effect on MCF10A cells. Our findings, therefore, suggest that TACC3 may play an important role in the progression from DCIS to invasive breast cancer and that targeting TACC3 could be a promising new therapeutic strategy for DCIS patients.
Citation Format: Loredana Campo, Maya Mathew, Eun-Kyoung breuer, William Small. The role of TACC3 in the progression from ductal carcinoma in situ to invasive 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 3019. doi:10.1158/1538-7445.AM2017-3019
Abstract 303: Oncogenic activity of amplified miniature chromosome maintenance 8 in human malignancies
Authors: Luo Jian-Hua , He Dong-Mei , Ren Baoguo , Yu Yan 
Published: July 2017

Abstract
Miniature chromosome maintenance (MCM) proteins play critical roles in DNA replication licensing, initiation and elongation. MCM8, one of the MCM proteins playing critical role in DNA repairing and recombination, was found to have over-expression and increased DNA copy number in a variety of human malignancies. The gain of MCM8 is associated with aggressive clinical features of several human cancers. Increased expression of MCM8 in prostate cancer is associated with cancer recurrence. Forced expression of MCM8 in RWPE1 cells, the immortalized but non-transformed prostate epithelial cell line, exhibited fast cell growth and transformation, while knocked down of MCM8 in PC3, DU145 and LNCaP cells induced cell growth arrest, and decreased tumor volumes and mortality of severe combined immunodeficiency mice xenografted with PC3 and DU145 cells. MCM8 bound cyclin D1 and activated Rb protein phosphorylation by cyclin-dependent kinase 4 in vitro and in vivo. The cyclin D1/MCM8 interaction is required for Rb phosphorylation and for S phase entry in cancer cells. As a result, our study showed that copy number increase and overexpression of MCM8 may play critical roles in human cancer development.
Note: This abstract was not presented at the meeting.
Citation Format: Jian-Hua Luo, Dong-Mei He, Baoguo Ren, Yan Yu. Oncogenic activity of amplified miniature chromosome maintenance 8 in human malignancies [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 303. doi:10.1158/1538-7445.AM2017-303
Abstract 3030: Mutant p53-driven metastasis explored utilizing a traceable, conditional osteosarcoma model
Authors: Pourebrahimabadi Rasoul , Zhang Yun , McArthur Mark J. , Lozano Guillermina 
Published: July 2017

Abstract
TP53 is the most frequently mutated gene in cancer and missense mutations in particular account for the majority of mutations. Mutant p53 proteins exert oncogenic Gain-of-Function (GOF) properties that contribute to increased migration and invasion in culture and metastasis in vivo. To elucidate how mutant p53 drives metastasis, we developed a traceable somatic osteosarcoma model that initiates with a single p53 mutation (p53R172H or p53R245W), or p53 loss specifically in osteoblasts using Osx-cre. To mark tumor cells, we utilized the mTmG allele which expresses membrane-targeted Tomato (mT) prior to Cre-mediated excision and membrane-targeted green fluorescent protein (mG) after excision so the tumor cells become GFP+ and the stromal cells remain RFP+. In this high penetrant, short latency mouse model, tumor micro-metastasis can be detected by GFP expression in the context of a normal stroma and immune system. The cohort has developed osteosarcoma with complete penetrance and an average survival of 304± 65 day. We observed metastasis in 55% of p53 mutant osteosarcomas which was significantly higher than 26% metastasis observed in p53 null tumors (p&lt;0.01). In p53 mutant osteosarcomas, the metastasis rate was found significantly associated with low p53 copy number. Spectral karyotyping (SKY) on early passage cells derived from somatic p53 mutant tumors exhibited marked aneuploidy with modal chromosome numbers near tetraploid. To characterize the transcriptional profile associated with mutant p53 GOF, we analyzed and compared the RNA-Seq transcriptomes of eight tumors derived from p53R172H mutant mice with eight p53 null tumors. Comparative analysis of gene expression identified a signature of snRNA genes to be strongly associated with mutant p53 gain of function. Functional annotation of upregulated genes in mutant tumors was also highly enriched for chromatin modifying enzymes. These findings contribute to our understanding of the role of mutant p53 GOF in metastasis. Our long term goal is to study how tumor-stromal interactions affect tumor development and metastasis. This understanding will have broad translational significance in diagnosis and treatment of tumors with mutant p53.
Citation Format: Rasoul Pourebrahimabadi, Yun Zhang, Mark J. McArthur, Guillermina Lozano. Mutant p53-driven metastasis explored utilizing a traceable, conditional osteosarcoma model [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 3030. doi:10.1158/1538-7445.AM2017-3030
Abstract 3033: The PRL family of tyrosine phosphatases as a novel drug targets in acute lymphoblastic leukemia
Authors: Blackburn Jessica S. 
Published: July 2017

Abstract
The aggressive and unpredictable behavior of acute lymphoblastic leukemia (ALL) presents a major clinical challenge in both the pediatric and adult setting. The development of new and better chemotherapies for this disease requires a detailed understanding of the genes and pathways that drive ALL malignancy. Phosphatases are emerging as new drug targets with important roles in leukemia progression. To determine the extent to which phosphatases play a role in ALL malignancy, we used CRISPR/Cas9 to knock out expression of 255 individual phosphatases in human T-cell acute lymphoblastic leukemia cell lines and screened for deleterious effects on cell viability. Top hits from this screen included the protein tyrosine phosphatase type IVa family, also known as the PRLs. PRL3 is genomically amplified in a subset of human T-ALL, and more than 50% of human ALL patients have significantly higher expression of PRL2 and/or PRL3, compared to normal lymphocytes, suggesting that these PRLs may play an important role in ALL malignancy. Transgenic Myc-induced ALL models in zebrafish showed that overexpression of PRL2 and PRL3 significantly shortened latency of primary and relapse ALL, enhanced leukemia stem cell self-renewal (PRL2) and prevented apoptosis after standard chemotherapy treatment (PRL3). Finally, a specific PRL inhibitor strongly induced apoptosis of PRL-expressing ALL cells in a dose-dependent manner, in both zebrafish models in vivo and human cell lines in vitro. We have identified several FDA-approved, general phosphatase inhibitors that have potent anti-PRL activity and are capable of killing ALL cells in vitro. Current work is focused on moving these inhibitors into pre-clinical testing using patient-derived xenografts. Pull-down approaches are also being used to identify the substrates of PRL phosphatase activity that are critical to ALL survival and may represent new, tractable drug targets for the treatment of ALL. &lt;!–EndFragment–&gt;
Citation Format: Jessica S. Blackburn. The PRL family of tyrosine phosphatases as a novel drug targets in acute lymphoblastic leukemia [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 3033. doi:10.1158/1538-7445.AM2017-3033