bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 651: Male mouse model of canine and human inflammatory breast cancer (IBC)
Authors: Caceres Sara , Peña Laura , Illera Maria J. , Silvan Gema , de andres Paloma J. , Gao Hui , Woodward Wendy A. , Reuben James M. , Illera Juan C. 
Published: July 2016

Abstract
Inflammatory breast cancer (IBC) is an aggressive type of breast cancer with poor survival in women. Canine IBC has been proposed as a good surrogate model for the study of the human disease. Male breast cancer is a rare disease, accounting for less than 1% of all malignancies in men. Although rarely, IBC has been also found in men. The aim was to evaluate the capacity of male SCID mice to develop IBC tumors after the injection of canine and human IBC cell lines (IPC-366 and SUM149, respectively). Eighty SCID mice: 40 male and 40 females, 6-8 weeks old were used. Suspensions of 106 IPC-366 and SUM149 cells were implanted subcutaneously into the fourth inguinal mammary gland in 20 male and 20 female mice (of each cell line), respectively. Mice were inspected twice a week for the development of tumors. Tumors were monitored by palpation and measured by calipers. Mice were sacrificed when tumors reached 1.5 cm3 and tumors and organs were removed for immunohistochemical (IHC) characterization. A portion of tumor was used for hormonal analysis (Progesterone, Estradiol, Estrone sulphate, Testosterone, Androstenedione). Results revealed that IPC-366 reproduced tumors in 90% (male) vs 100% (female) after 2 weeks p.i. SUM149 reproduced tumors in 40% (male) vs 80% (female) at 4 weeks p.i. Both cell lines produced metastasis in lungs. Higher metastatic rates found in females than in males (IPC-366: 90% vs 20%; SUM149: 80% vs 50%). EIA hormonal analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors (p&lt; 0.05). IHC analysis revealed that male and female tumors shared immunophenotipic characteristics. All xenografts were highly proliferative (high Ki-67 indexes), triple negative (ER-, PR-, HER-2-), vimentin positive and contained less than 10% of cells positive to AE1-AE3 and CK-14. In conclusion, IPC-366 and SUM149 cell lines can reproduce tumors in male mice capable of metastasize. Male and female xenograft models shared immunophenotypic characteristics. Male mice model would be useful for future IBC research using a different endocrine environment that could help to better understand the androgens function in canine and human IBC.
Citation Format: Sara Caceres, Laura Peña, Maria J. Illera, Gema Silvan, Paloma J. de andres, Hui Gao, Wendy A. Woodward, James M. Reuben, Juan C. Illera. Male mouse model of canine and human inflammatory breast cancer (IBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 651.
Abstract 653: Identification of metastasis promoting genes using the PiggyBac insertional mutagenesis system
Authors: Tinghu Qiu N. , Vera Ramirez Laura , Rad Roland , Green Jeffrey E. 
Published: July 2016

Abstract
The Myc oncogene is overexpressed in approximately 30% of human breast cancers. Mice carrying the mammary tumor virus LTR/c-myc (MMTV-c-Myc) develop mammary tumors, but display a relatively low rate of metastases to the lung. However, not all cells that express the transgene develop neoplasms indicating that Myc-induced tumorigenesis requires additional cooperating events for full transformation. To identify genes that cooperate with Myc-induced tumorigenesis leading to the acceleration of tumor progression or an increase in metastases in MMTV-Myc transgenic mice, we have employed the PiggyBac (PB) transposon system.
The PiggyBac system used in our studies was (developed by Rad et al, Science, 2010) is composed of two elements, the ATP-1 PiggyBac transposon and transposase. ATP-1 transposons are mobile DNA elements that can randomly integrate throughout the genome in the presence of transposase resulting in the activation or loss of gene function. The insertion sites can be identified through sequencing. It has been used successfully for genomic modification of cells in vivo leading to cancer gene discovery. In order to better adapt the PB system for studing mammary gland biology, we have designed a system to express a hyperactive transposase and luciferase specifically in the mammary gland using the MMTV LTR (MMTV-hyTPase-luc). The efficiency of MMTV-hyTPase-luc expression was first examined in vitro by transfection with an ATP-1 containing plasmid using the HC11 mouse mammary epithelial cell line. Selection for integration of ATP1 in the cells using puromycin selection and crystal violet staining, RT-QPCR and luciferase assays confirmed that MMTV-hyTPase-luc led to efficient integration of ATP-1 into the HC11 cells. HC11 cell proliferation further increased in the presence of dexamethasone, a hormone that stimulates MMTV promotor function. The MMTV-HyPB-Luc construct was subsequently used to generate transgenic mice and multiple founder lines are being analyzed for mammary specific transposase expression. The best expressing line will be crossed with MMTV-cMyc mice and mice carrying multiple copies of the ATP1 transposon. Transposon integration sites will be determined from tumors or metastases in mice with accelerated tumor development and/or increased metastases compared to controls. Further molecular characterization and validation of candidate genes will identify novel genes that cooperate with Myc to augment tumorigenesis and metastases.
Citation Format: Qiu N. Tinghu, Laura Vera Ramirez, Roland Rad, Jeffrey E. Green. Identification of metastasis promoting genes using the PiggyBac insertional mutagenesis system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 653.
Abstract 66: High-throughput screening using patient derived tumor cell to conduct personalized medicine
Authors: Kim Seung T. , Park Charny , Kim Sun , Lee Won , Park Joon , Kim Kyoung-Mee , Park Woongyang , Lee Jeeyun , park young , Jang Jiryeon 
Published: July 2016

Abstract
Background:
Patient-derived cell (PDC) model is one of prospective technologies to investigate drug response for precision medicine. Previously drug sensitivity derived PDC model has been studied in colorectal cancer organoid culture or lung cancer model. They revealed that PDC model recapitulates genomic characteristic and drug high-throughput screening is amenable. We established PDC models from metastatic cancer cohort of multiple cancer types, and revealed genomic characteristics and matched drug response.
Method:
Target sequencing was performed using OncoPanel. We called SNV, and CNV from target sequencing using GATK, then clinically unassociated SNPs were eliminated. Somatic submodules were identified from integrative variant profiles using HotNet referring HPRD. Drug high-throughput screening was performed SEMCO platform. In order to identify sensitive drug and variant gene pairs, drug sensitivity was tested by ANOVA using IC50 values.
Result:
Target sequencing of exome were generated from our 165 PDC models, and drug high-throughput screening was performed from 30 PDCs and ant-cancer 15 drugs. We tried integrative analysis approaches from genomic profile including mutation and copy number alteration, and identified genomic modules related with Fanconi, Hedgehog, FGFR receptor, Cytokine-cytokine receptor pathway. Variants of known oncogenes were successfully identified in MET, BRAF, FGFR and PIK4CA. Especially novel and recurrent mutations were identified in FGFR2, and corresponding samples indicated AZD4547 sensitivity as well as known drug response case such as BRAF V600E targeting Vemurafenib.
Conclusion:
Our study explains that PDC cohort sustains cancer related pathways, and its drug response follows genomic features. It is expected that our research would contribute to facilitate precision medicine from PDC model to utilize genomics and drug response.
Citation Format: Seung T. Kim, Charny Park, Sun Kim, Won Lee, Joon Park, Kyoung-Mee Kim, Woongyang Park, Jeeyun Lee, young park, Jiryeon Jang. High-throughput screening using patient derived tumor cell to conduct personalized medicine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 66.
Abstract 660: Modelling conventional and serrated colorectal tumorigenesis by altering the Wnt and MAPK signaling pathways
Authors: Whitehall Vicki , Fernando Winnie , McKeone Diane , Bettington Mark , Pearson Sally , Bond Catherine , Leggett Barbara 
Published: July 2016

Abstract
Background. The majority of conventional colorectal adenomas are initiated by activation of the Wnt signal, whilst activation of the MAPK pathway is associated with progression to cancer. In contrast, sessile serrated adenomas are initiated by activation of the MAPK signaling pathway due to mutation of the BRAF oncogene, whilst the Wnt pathway is activated at the transition to dysplasia. We hypothesised that whilst both the Wnt and MAPK pathways play key roles in colorectal tumorigenesis, the order in which these signaling pathways are activated would determine the morphology of the lesion arising.
Methods. To test this hypothesis, we utilised a conditional BRAF mutant mouse model crossed with an inducible Cre driven by the murine Villin gene promoter, to restrict Cre expression and induction of the BRAF mutation to the intestine. The MAPK pathway was activated two weeks after birth, whilst activation of the Wnt signal was achieved using APCMin mice or the intestinal carcinogen azoxymethane. Morphology and number of lesions was confirmed by histologically examination. Nuclear β-catenin immunostaining provided a surrogate for activation of the Wnt signal.
Results. Induction of the BRAF mutation resulted in the rapid and sustained development of widespread intestinal hyperplasia. Murine serrated adenomas (mSA) mimicking the morphology of human traditional serrated adenomas were observed by 5 months and by 10 months 8/18 (44.4%) mice had developed mSA, primarily in the duodenum. Activation of the Wnt pathway using azoxymethane dramatically accelerated the serrated phenotype in both the small intestine (2.9 mSA per mouse, P&lt;0.01) and colon (3.1 mSA per mouse, P&lt;0.05) by 3 months. The MAPK and Wnt pathways also synergized in APCMin mice, increasing the average number of conventional adenomas per mouse from 2.1 to 78.8 (P&lt;0.001).
Conclusion. The rapid induction of hyperplasia and exclusive development of serrated lesions demonstrates that BRAF mutation is a key molecular event underlying initiation of serrated neoplasia. Importantly, we have demonstrated that activation of the MAPK pathway through BRAF mutation is sufficient for commitment to the serrated pathway and that whilst subsequent activation of the Wnt signal can accelerate tumorigenesis, it is not sufficient to override the existing serrated morphology.
Citation Format: Vicki Whitehall, Winnie Fernando, Diane McKeone, Mark Bettington, Sally Pearson, Catherine Bond, Barbara Leggett. Modelling conventional and serrated colorectal tumorigenesis by altering the Wnt and MAPK signaling pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 660.
Abstract 664: Insulin receptor signaling contributes to mammary tumorigenesis in mice
Authors: Poloz Yekaterina , Mouaaz Samar , Lam Sonya , Stambolic Vuk 
Published: July 2016

Abstract
A recent convergence of clinical and epidemiological evidence suggests that hyperinsulinemia associated with obesity and type 2 diabetes leads to higher incidence and poor outcome of breast cancer (BC). To probe the role of insulin signaling in BC, we created the MMTV-driven polyoma middle T BC model mice with an inducible mammary epithelium-specific deletion of the insulin receptor (INSR). Deletion of INSR in the mammary gland considerably reduced the mammary tumour burden in the INSR knockout mice as compared to the INSR wildtype controls, without affecting the tumour onset. The average weight of individual tumours was similar across the genotypes, suggesting that deletion of INSR affected the tumour initiation potential of the epithelial cells rather than tumour growth. Deletion of INSR also affected the metastasis of mammary tumours to the lung, with the INSR knockout mice presenting with half the number of metastases compared to the INSR wildtype controls. Our ongoing efforts are focused on mapping the signaling events downstream of the INSR that govern tumour initiation and metastasis in our mice, as well as modeling the impact of obesity on tumors in this model system, with the ultimate goal of identifying the role of INSR signaling in BC development and progression.
Citation Format: Yekaterina Poloz, Samar Mouaaz, Sonya Lam, Vuk Stambolic. Insulin receptor signaling contributes to mammary tumorigenesis in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 664.
Abstract 665: Blocking IL-1-NF-kB axis inhibits Kras-induced pancreatic ductal adenocarcinoma
Authors: Ling Jianhua , Fu Jie , Wu Min , Cao Yu , Chiao Paul 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the USA with approximately 50 000 new cases and 40 000 deaths in 2015.The 5-year survival rate has remained at 5% for the past three decades and the median survival duration is less than 6 months. The very high rate of mutant Kras occurs in pancreatic cancer (&gt;90%) and pancreatic intraepithelial neoplasia (panIN) (&gt;50%). However, the key signaling pathway of downstream Kras remains unidentified.
We previously uncovered that the NF-êB signaling pathway was constitutively activated in most PDAC specimens and pancreatic cancer cell lines. More recently, our results showed that constitutive NF-êB activity in PDAC was induce by IL-1 autocrine mechanism. IL-1/p62 feedforward loops that initiated by the mutant Kras sustained NF-êB activity and were required for pancreatic cancer development. Therefore, we hypothesize that blocking IL-1 - NF-êB signaling pathway will inhibit Kras-induced pancreatic ductal adenocarcinoma.
To identify the mechanistic role of mutant Kras-induced IL-1 expression in PDAC, we generated genetically engineered mice of Pdx1-cre/Kras LSL-G12D/p53 M/+IL-1á−/−. Our findings revealed that these mutant mice had developed significantly less PDAC number and a significantly delayed PDAC at old ages. Furthermore, we assess the effect of pharmacological IL-1R1 antagonist (anakinra) in human pancreatic cancer cell lines and orthotopic pancreatic cancer mouse. We found that IL-1R1 antagonist significantly decreased NF-êB activity and inhibited cell proliferation, migration and invasion. More interestingly, the combinational treatment IL-1R1 antagonist plus gemcitabine significantly reduced the tumor burden in orthotopic pancreatic cancer mouse.
These results suggested that pharmacologically targeting IL-1á may provide a novel therapeutic approach for pancreatic cacner.
Citation Format: Jianhua Ling, Jie Fu, Min Wu, Yu Cao, Paul Chiao. Blocking IL-1-NF-kB axis inhibits Kras-induced pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 665.
Abstract 677: EML4-ALK fusion gene expressing transgenic mouse for lung cancer model
Authors: Pyo Kyoung-Ho , Kim Hye Ryun , Lim Sun Min , Yun Mi Ran , Kim Sung-Moo , Kim Hwan , Kang Han Na , Lee Ji Min , Kim Sang Gyun , Cho Byoung Chul 
Published: July 2016

Abstract
Background: EML4-ALK is a fusion-type protein typrosin kinase that is generated in lung cancer. We have established transgenic mouse line. The surfactant protein C gene (SPC) is only expressed in alveolar epithelial cells. We applied SPC promoter on encoded human-EML4-ALK gene. Normally, EML4-ALK gene is silenced when LoxP-PGK-LoxP gene is turned on. When Cre recombinase is present with the specific inducer, tamoxifen, EML4-ALK gene is expressed in alveolar epithelial cell, and converses to lung cancer.
Materials and Methods: For generation of EML4-ALK fusion transgenic mouse, a cDNA fragment encoding FLAG tagged EML4-ALK (variant 1) was ligated to end of the CMV-LoxP-PGK-LoxP. The expression cassette was injected into pronuclear-stage embryos of B6 mouse to generate Tg mouse. Transgenic mouse was prepared for interbreed with KI mouse (SPC-CreER2T-trTA-NeoR). The KI-Tg fusion mouse was confirmed by genotyping, then the mouse was injected with tamoxifen (cre recombinase inducer) intraperitoneally. The lung tumors were observed by MRI or CT. The lung pathology was analyzed by immunohistochemistry and hematoxylin & eosin staining. For confirmation of EML4-ALK protein expression, western blot was performed in different organs. EML4-ALK tumor-bearing mouse was treated with ALK tyrosine kinase inhibitor (TKI) for 2 weeks and tumor shrinkage was measured.
Results: EML4-ALK tumor was observed after one week. Tumor nodules were widely observed in all lung lobes. Pathologically, the histologic type was adenocarcinoma and had homology to patient tissue on H&E stain. We confirmed EML4-ALK expression in different organs including lung, heart, liver, stomach, kidney, colon and brain. EML4-ALK (120kDa) was strongly expressed in lung, but not
in other organs. Indeed, ALK and Flag expression were observed in tumor region by immunohistochemistry. The EML4-ALK tumor bearing mice were treated with ALK TKI for 2 weeks. The ALK TKI-treated mice showed dramatic shrinkage of tumors and showed gain in body weight.
Conclusions: EML4-ALK Tg mouse was successfully established. The benefits of the model compared to a previous conditioned Tg mouse model are (1) no need to treat Cre inducer daily, and (2) short duration (approximately 1 week) of tumorigenesis. We confirmed dramatic tumor shrinkage after treatment with ALK TKI. This model provides a strong preclinical model for testing ALK TKIs in lung cancer.
Citation Format: Kyoung-Ho Pyo, Hye Ryun Kim, Sun Min Lim, Mi Ran Yun, Sung-Moo Kim, Hwan Kim, Han Na Kang, Ji Min Lee, Sang Gyun Kim, Byoung Chul Cho. EML4-ALK fusion gene expressing transgenic mouse for lung cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 677.
Abstract 680: Diet-induced obesity promotes tumor aggressiveness in genetically engineered mouse models of endometrial hyperplasia/cancer
Authors: Clark Leslie H. , Zhou Chunxiao , Montgomery Stephanie A. , Gehrig Paola A. , Bae-Jump Victoria 
Published: July 2016

Abstract
Objective: To determine the effect of diet-induced obesity on the development of endometrial hyperplasia and cancer in genetically engineered mouse models.
Methods: The PTEN heterozygous mouse model for endometrial hyperplasia and the LKB1/p53 endometrioid endometrial cancer mouse model were used. Mice were divided into two dietary groups and fed either a high-fat diet (HFD, 60% calories from fat, obese) or a low-fat diet (LFD, 10% calories from fat, lean) beginning at 3 weeks of age until sacrifice at 32 weeks (PTEN model) and 12 weeks (LKB1/p53 model). At the time of sacrifice, mouse weight and uterine/tumor size were documented. A dedicated mouse pathologist reviewed uterine pathology. For the PTEN heterozygous mouse model, uterine pathology was determined to be simple hyperplasia (SH) if increased number of simple tubular glands were seen without atypia. Complex hyperplasia (CH) was defined as branching, papillary lumenal infoldings, or back-to-back glandular crowding with or without nuclear atypic.
Results: A total of 30 PTEN mice were examined, 14 in the obese group and 16 in the lean group. The HFD-fed mice were larger than the LFD-fed mice with a mean weight of 38.1 gm compared to 29.7 gm (p&lt;0.001). There was no difference in uterine weight between the obese and lean mice, 0.30 versus 0.34 gm, respectively (p = 0.76). The lean mice were more likely to develop SH, 44% (n = 7) versus 7% (n = 1) in the obese group (p = 0.04). Of the obese mice, 57% (n = 8) developed CH (± atypia) compared to 31% (n = 5) of the lean mice (p = 0.16). A total of 35 LKB1/p53 mice were examined with 21 in the obese group and 14 in the lean group. The obese LKB1/p53 mice were larger (32.8 gm) than the lean mice (24.0 gm) (p = 0.033). The majority of the LKB1/p53 mice developed endometrioid adenocarcinoma with increased tumor size in the obese group (2.1 gm) versus lean group (0.79 gm) (p = 0.04).
Conclusions: Diet-induced obesity led to increased mean body weight in both mouse models. In the PTEN heterozygous mouse model, a trend towards more complex endometrial hyperplasia was found in the obese group along with a higher rate of simple hyperplasia in the lean group. Increased endometrial tumor size was seen in the obese versus lean LKB1/p53 mice, suggesting that obesity may lead to increased aggressiveness in endometrial cancer.
Citation Format: Leslie H. Clark, Chunxiao Zhou, Stephanie A. Montgomery, Paola A. Gehrig, Victoria Bae-Jump. Diet-induced obesity promotes tumor aggressiveness in genetically engineered mouse models of endometrial hyperplasia/cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 680.
Abstract 685: Selective inhibitor of nuclear export (SINE) compounds prevent migration and proliferation of triple negative breast cancer (TNBC) cells by restoring expression of ARRDC3
Authors: Soung Young Hwa , Kashyap Trinayan , Nguyen Thalia , Landesman Yosef , Chung Jun 
Published: July 2016

Abstract
Arrestin-related domain-containing protein-3 (ARRDC3) is one of 6 mammalian arrestins, which has been shown to possess tumor suppressor activity by inducing degradation of phosphorylated â2-adrenergic receptor (â2 AR) and integrin â4 (ITG â4). Our previous studies demonstrated that Sirt2 epigenetically silenced expression of ARRDC3 in TNBC cells and overexpression of ARRDC3 significantly reduced their invasive potential. Therefore, we hypothesized that compounds, which restore ARRDC3 expression levels could serve as novel therapeutic options for TNBC. To test this, we examined the ability of SINE compounds: KPT-185 and KPT-330 (selinexor), to effectively restore ARRDC3 expression. We observed that KPT-185 and selinexor significantly induced ARRDC3 expression and inhibited the proliferation and the invasiveness of the TNBC cell lines MDA-MB-231 and MDA-MB-468 in vitro. In vivo, selinexor inhibited the tumor growth of MDA-MB-231 and MDA-MB-468 xenografts by nearly 100% compared with vehicle treated animals. Furthermore, immunohistochemical analysis of TNBC tumors from selinexor treated mice revealed increased ARRDC3 expression versus vehicle treated animals. Our results suggest that restoration of ARRDC3 expression is an important antineoplastic mechanism of SINE compounds in TNBC and suggest that selinexor could be an effective treatment against tumors with downregulated ARRDC3.
Citation Format: Young Hwa Soung, Trinayan Kashyap, Thalia Nguyen, Yosef Landesman, Jun Chung. Selective inhibitor of nuclear export (SINE) compounds prevent migration and proliferation of triple negative breast cancer (TNBC) cells by restoring expression of ARRDC3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 685.