bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-211: Targeting triple negative breast cancer by using non-oncologic drug targets.
Authors: Bernemann Christof , Huelsewig Carolin , von Wahlde Marie-Kristin , Kiesel Ludwig , Liedtke Cornelia 
Published: August 2014

Abstract
Background:
Triple negative breast cancer (TNBC) is defined by the lack of estrogen-receptor alpha (ERα) and pro-gesterone receptor (PGR) expression as well as absence of human epidermal growth factor receptor2 (HER2/neu) overexpression. This type of breast cancer is characterized by a poor prognosis and sig-nificantly reduced survival rate compared to other breast cancer subtypes. This is mostly due to the lack of targeted agents like endocrine or anti HER2 targets.
Gene expression analysis revealed that different molecular targets are overexpressed in triple nega-tive breast cancer compared to other breast cancer subtypes. Therefore, these drug targets hold great potential for newly personalized therapeutic approaches in TNBC as well as other cancer types.
Methods:
Based on a list previously published (Liedtke et al., Cancer Res 2009) we defined the enzyme ALOX5 (arachidonate 5-lipoxygenase) as being a prominent new potential drug target. By using a set of known inhibitors of ALOX5 we deeply analyzed the effect on triple negative breast cancer cells as well as other breast cancer subtypes.
Results:
We firstly could show, that expression of ALOX5 correlates with the subtype of triple negative breast cancer, by trend. Treatment with meclofenamic acid additionally, showed significant decrease of proliferative capacity in at least some triple negative breast cancer cell lines.
Conclusion:
We could show that - in case of ALOX5 - its expression correlates with the triple negative breast cancer subtype by trend. Therefore, an inhibition of this molecular target might provoke anti prolife-rative effects on triple negative breast cancer cells. Actually, treatment with meclofenamic acid - a drug already used for joint, arthritis, muscular pain - showed reduction of proliferation in triplen negative breast cancer cells. Whether this effect relies on inhibition of ALOX5 or its function has to be analyzed further.
Citation Format: Christof Bernemann, Carolin Huelsewig, Marie-Kristin von Wahlde, Ludwig Kiesel, Cornelia Liedtke. Targeting triple negative breast cancer by using non-oncologic drug targets. [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 LB-211. doi:10.1158/1538-7445.AM2013-LB-211
Abstract LB-216: Acquired lapatinib resistance in HER2-positive breast cancer cells is associated with up-regulation of mutant PI3K and/or secondary PI3K mutation.
Authors: Brady Samuel , Zhang Jian , Yu Dihua 
Published: August 2014

Abstract
Resistance to the HER2 kinase inhibitor lapatinib is a major challenge in the treatment of HER2-positive breast cancer. To model acquired lapatinib resistance we generated two drug-resistant cell lines by extended exposure to lapatinib. Both HER2-amplified parental cell lines (BT474 and UACC893) possesssed PI3K p110α activating mutations, and were lapatinib-sensitive. Both lapatinib-resistant (LapR) cell lines possessed 2- to 3-fold increased levels of the PI3K p110α subunit and increased levels of phosphorylated Akt during lapatinib treatment. p110α increase occurred through gene amplification in the BT474 LapR cells and post-transcriptional protein increase in the UACC893 LapR cells. One of the two cell lines (BT474 LapR) also acquired a hotspot strong activating mutation (E542K) in p110α, whereas the parental cells possessed only a weak activating mutation (K111N). Mutant PI3K (E542K or H1047R) was sufficient to promote lapatinib resistance. Moreover, knockdown of p110α, but not p110β, sensitized both LapR cell lines to lapatinib. PI3K inhibitors were also effective in overcoming drug resistance. To our knowledge, this is the first suggestion of this dose-dependent effect of mutant p110α in lapatinib resistance and the first identified instance of post-transcriptional up-regulation of mutant p110α in lapatinib resistance. These findings may explain why some HER2-positive, PI3K p110α-mutant breast cancers are lapatinib-sensitive while others are lapatinib-resistant (increased level of p110α). Our findings also reinforce those of others indicating that HER2-positive breast cancer patients with mutant PI3K should be co-treated with HER2-targeting and PI3K-targeting therapies in order to prevent or overcome drug resistance.
Citation Format: Samuel Brady, Jian Zhang, Dihua Yu. Acquired lapatinib resistance in HER2-positive breast cancer cells is associated with up-regulation of mutant PI3K and/or secondary PI3K mutation. [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 LB-216. doi:10.1158/1538-7445.AM2013-LB-216
Abstract LB-236: Patient derived xenografts as high-fidelity genomic models for advanced breast cancer.
Authors: Li Shunqiang , Shen Dong , Li Ding , Yu Tao , Luo Jingqin , Hoog Jeremy , McMichael Joshua , Miller Chris , Larson Dave , Bose Ron , Fulton Bob , Wilson Rick , Perou Charles , Mardis Elaine , Ellis Matthew 
Published: August 2014

Abstract
A limitation of recent genome studies is that they have almost exclusively focused on early stage untreated samples. Consequently the genomic landscape of advanced and treatment-resistant disease is poorly documented, even though Stage 4 patients stand to benefit most from new therapeutic approaches. To address this issue we developed a panel of patient-derived xenografts (PDX) from Stage 3 and 4 patients with treatment-resistant disease to create a platform for detailed molecular and pharmacological investigation. Recently we reported a whole genome sequencing study of a single example of a breast cancer primary, brain metastasis and PDX “trio” demonstrating that the PDX model efficiently captured almost all of the genome-wide variants observed in the tumor and was enriched for mutations present in the metastatic sample (Ding, Ellis et al., Nature 2010). We now extend these findings by conducting massively parallel sequencing of 13 additional PDX models from a diverse set of locally- advanced or Stage 4 breast cancers, all of whom subsequently died from their disease. Structural variants (deletions, inversions and translocations) were remarkably stable and although new single nucleotide variants were observed post-engraftment, most were either non-coding or not expressed and only one had established functionality (K-RAS). PDX models are therefore high-fidelity genomic models for the biological and pharmacological study of complex, often tumor-unique somatic events responsible for lethal drug-resistant advanced breast cancer.
Citation Format: Shunqiang Li, Dong Shen, Ding Li, Tao Yu, Jingqin Luo, Jeremy Hoog, Joshua McMichael, Chris Miller, Dave Larson, Ron Bose, Bob Fulton, Rick Wilson, Charles Perou, Elaine Mardis, Matthew Ellis. Patient derived xenografts as high-fidelity genomic models for advanced breast 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 LB-236. doi:10.1158/1538-7445.AM2013-LB-236
Abstract LB-237: Human and microbial transcriptomics from lean and obese individuals with colorectal cancer: A comparison of Total and Poly A RNA sequencing from clinical samples.
Authors: Grice Desma M. , Bauer Denis C. , Duesing Konsta , Li Dongmei , Greenfield Paul , Nielsen Sarah , Draganic Brian , Smith Steve , Pockney Peter , Scott Rodney , Hannan Garry N. 
Published: August 2014

Abstract
Australia and New Zealand have the highest worldwide CRC incidence with CRC being the 2nd most commonly diagnosed cancer and the 3rd most common cause of cancer death among both men and women. CRC is a complex disease arising from the impact of environmental factors, including diet and lifestyle choices on different genetic backgrounds. Obesity and type 2 diabetes are significant risk factors for CRC, the levels of which are increasing in Australia. As a consequence CRC is projected to increase, being the most common Australian cancer by 2025. While the association of obesity with CRC has been reported by a number of studies, the mechanism\s that contribute to CRC development in the context of obesity are unknown. Understanding these mechanisms and potential genetic susceptibility is crucial for developing effective intervention and screening strategies. Recent evidence suggests that gut microbial communities are altered in obese individuals, resulting in a change in the predominant species and overall loss of community diversity but it is unknown if these changes impact CRC development or progression. We have established a comprehensive tissue, blood and microbial collection from 150 lean and obese colorectal cancer patients in the Hunter Region, Australia and commenced an integrative pilot next generation sequencing project to begin to unravel the link between obesity and CRC. Twelve individuals (6 lean and 6 obese) were selected for complementary next-generation sequencing; generating matched sequencing data sets (Total RNA-seq, Poly A RNA-seq, microbial RNA-seq and exome-seq) from normal colon, colon tumor, adipose and digesta samples samples. For this purpose, we have developed a method for simultaneously isolating human and microbial RNA from gut lumen of sufficient quality and quantity from limited material. Results presented will evaluate the differences in host and microbial transciptomics in normal colon and tumor tissue of lean and obese individuals with CRC and methodological comparisons between Total RNA-seq and Poly A RNA-seq will be reported.
Citation Format: Desma M. Grice, Denis C. Bauer, Konsta Duesing, Dongmei Li, Paul Greenfield, Sarah Nielsen, Brian Draganic, Steve Smith, Peter Pockney, Rodney Scott, Garry N. Hannan. Human and microbial transcriptomics from lean and obese individuals with colorectal cancer: A comparison of Total and Poly A RNA sequencing from clinical samples. [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 LB-237. doi:10.1158/1538-7445.AM2013-LB-237
Abstract LB-248: BRAFV600E remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration.
Authors: Flockhart Ross J. , Webster Dan E. , Qu Kun , Mascarenhas Nicholas , Kovalski Joanna , Kretz Markus , Paul Khavari A. 
Published: August 2014

Abstract
Aberrations of protein-coding genes are a focus of cancer genomics; however, the impact of oncogenes on expression of the ~50% of transcripts without protein-coding potential, including long noncoding RNAs (lncRNAs), has been largely uncharacterized. Activating mutations in the BRAF oncogene are present in &gt;70% of melanomas, 90% of which produce active mutant BRAF(V600E) protein. To define the impacts of oncogenic BRAF on the melanocyte transcriptome, massively parallel cDNA sequencing (RNA-seq) was performed on genetically matched normal human melanocytes with and without BRAF(V600E) expression. To enhance potential disease relevance by verifying expression of altered genes in BRAF-driven cancer tissue, parallel RNA-seq was also undertaken of two BRAF(V600E)-mutant human melanomas. BRAF(V600E) regulated expression of 1027 protein-coding transcripts and 39 annotated lncRNAs, as well as 70 unannotated, potentially novel, intergenic transcripts. These transcripts display both tissue-specific and multi-tissue expression profiles and harbor distinctive regulatory chromatin marks and transcription factor binding sites indicative of active transcription. Coding potential analysis of the 70 unannotated transcripts suggested that most may represent newly identified lncRNAs. BRAF-regulated lncRNA 1 (BANCR) was identified as a recurrently overexpressed, previously unannotated 693-bp transcript on chromosome 9 with a potential functional role in melanoma cell migration. BANCR knockdown reduced melanoma cell migration, and this could be rescued by the chemokine CXCL11. Combining RNA-seq of oncogene-expressing normal cells with RNA-seq of their corresponding human cancers may represent a useful approach to discover new oncogene-regulated RNA transcripts of potential clinical relevance in cancer.
Citation Format: Ross J. Flockhart, Dan E. Webster, Kun Qu, Nicholas Mascarenhas, Joanna Kovalski, Markus Kretz, Khavari A. Paul. BRAFV600E remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration. [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 LB-248. doi:10.1158/1538-7445.AM2013-LB-248
Abstract LB-250: Development of a miR34-based cancer therapy.
Authors: Daige Chris , Wiggins Jason , Priddy Leslie , Kelnar Kevin , Zhao Jane , Bader Andreas , Brown David 
Published: August 2014

Abstract
miR-34 is a tumor suppressor miRNA that functions within the p53 pathway and regulates the expression of more than twenty oncogenes, including MET, MYC, WNT, and MYB. We have created a mimic of miR-34 called miR-Rx34 that induces cell cycle arrest, senescence, and apoptosis in cancer cells. Transient transfection of miR-Rx34 significantly reduces the proliferation of cancer cells derived from patients with liver, lung, breast, colon, and pancreatic cancers as well as melanoma, lymphoma, and multiple myeloma. miR-Rx34 has been encapsulated in an anionic liposome to produce a particle called MRX34 that has a diameter of ~120 nm. Intravenous injections of MRX34 causes dose-dependent increases in miR-34 levels in liver tumor, lung tumor, liver, lung, spleen, and other highly vascularized tissues in mice without inducing an immune response. Systemic delivery of MRX34 causes complete tumor regression in two orthotopic models of liver cancer. The exceptional potency of MRX34 likely results from its capacity to stimulate the p53 pathway and down-regulate genes in the wnt/B-catenin, MET, MAPK, and VegF pathways in liver tumors. The no adverse effects level observed for MRX34 in IND-enabling toxicology studies in monkeys and rats are 10-100-fold higher than the doses that produce complete tumor regression in mice, suggesting that the drug candidate will have a broad therapeutic window in cancer patients. Clinical studies with MRX34 that are expected to begin in early 2013 will provide the first measure of the therapeutic potential of a tumor suppressor miRNA.
Citation Format: Chris Daige, Jason Wiggins, Leslie Priddy, Kevin Kelnar, Jane Zhao, Andreas Bader, David Brown. Development of a miR34-based cancer therapy. [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 LB-250. doi:10.1158/1538-7445.AM2013-LB-250
Abstract LB-259: Arid1a loss in collaboration with PI3K pathway activation leads to ovarian tumorigenesis in mouse.
Authors: Guan Bin , Wang Tian-Li , Shih Ie-Ming 
Published: August 2014

Abstract
ARID1A encoding BAF250a is a recently identified tumor suppressor involved in chromatin remodeling. Inactivating somatic mutations occur in a wide variety of human cancers including ovarian carcinoma. Interestingly, ARID1A mutations significantly co-occur with either PIK3CA or PTEN mutations in human neoplastic tissues, suggesting a molecular collaboration of ARID1A and PI3K/PTEN pathways in tumor development. We tested this possibility in Arid1a knockout mice (n=10) and Arid1a/Pten double knockout mice (n= 12), in which Arid1a and Pten can be conditionally deleted in the mouse ovarian surface epithelium (OSE) by intra-ovarian bursal injection of Ad-Cre virus. Arid1a knockout mice did not develop discernable histopathological changes 12 months after Ad-Cre administration in OSE, a finding similar to Pten knockout mice as reported previously. In contrast, Arid1a/Pten double knockout mice developed ovarian tumors in 40% mice 6 months after Ad-Cre virus injection. The tumors effaced ovarian tissues, disseminated intraperitoneally and developed ascites. None of the tumors expressed detectable ARID1A and Pten immunoreactivity, while fibroblastic cells and OSE cells from control ovaries are positive for both markers. Although all the tumors appear poorly differentiated, 80% tumors were positive for cytokeratin 8, suggestive of an epithelial origin. The remaining 60% mice without grossly visible tumors showed hyperplasia of OSE in Ad-Cre treated ovaries but not in non-injected controls. The hyperplasia of OSE developed as early as 2 months after Ad-Cre administration. In summary, our results demonstrate that mutation of Arid1a requires a second hit to initiate tumorigenesis. Collaboration between Arid1a inactivation and PI3K/Pten pathway aberration is sufficient to induce OSE hyperplasia and to develop poorly differentiated carcinomas.
Citation Format: Bin Guan, Tian-Li Wang, Ie-Ming Shih. Arid1a loss in collaboration with PI3K pathway activation leads to ovarian tumorigenesis in mouse. [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 LB-259. doi:10.1158/1538-7445.AM2013-LB-259
Abstract LB-261: Mammary tumorigenesis in haploinsufficient Cripto-1 mice.
Authors: Rangel Maria Cristina , Raafat Ahmed , Castro Nadia P. , Klauzinska Malgorzata , Karasawa Hideaki , Baker Alyson , Callahan Robert , Salomon David S. 
Published: August 2014

Abstract
The embryonic gene Cripto-1 (Cr-1) is expressed at very low levels in normal adult tissues and detected at high levels in several human tumors. We have previously found that Cr-1 can facilitate the proteolytic intracellular processing of all four Notch receptors. Transgenic mice overexpressing the Notch4 intracellular domain (Int3) in the mammary gland under the control of the whey acidic protein (WAP) promoter rapidly develop mammary hyperplasias and undifferentiated mammary adenocarcinomas in aged nulliparous females and after multiple cycles of pregnancy. Eighty percent of WAP-Int3 females develop mammary tumors by the second pregnancy. To assess the contribution of Cr-1 in the hyperplasias and tumors that arise in transgenic WAP-Int3 mice, we developed a bi-transgenic mouse model lacking one allele of Cr-1, by crossing the knock-in Cr-1/LacZ mice (containing a promoter-less bacterial β-galactosidase gene which disrupts one of the Cr-1 alleles) to WAP-Int3 transgenic mice. We found a 90% reduction in the frequency of mammary hyperplasias in these Cr-1/LacZ/WAP-Int3 mice in comparison to WAP-Int3 mice. Additionally, in the absence of one allele of Cr-1, Int3-induced transformation of mouse mammary epithelial cells was delayed in vivo, and additional cycles of pregnancy were required to observe tumor growth. Notably, only 20% of the Int3/Cr-1 haploinsufficient mice developed mammary tumors by the second pregnancy, as compared to 80% of those mice that preserve two alleles of Cr-1. The few tumors derived from these mice also showed a significantly more differentiated histology in comparison to those tumors that arose from mice preserving both alleles of Cr-1. We are currently generating a mouse model which conditionally lacks the two alleles of Cr-1 in the mammary gland, what should better address our question regarding the functional significance of Cr-1 in the development of Int3-induced mammary tumorigenesis.
Citation Format: Maria Cristina Rangel, Ahmed Raafat, Nadia P. Castro, Malgorzata Klauzinska, Hideaki Karasawa, Alyson Baker, Robert Callahan, David S. Salomon. Mammary tumorigenesis in haploinsufficient Cripto-1 mice. [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 LB-261. doi:10.1158/1538-7445.AM2013-LB-261
Abstract LB-266: SIRT1 governs GnRH neuron migration and The Kallmann syndrome phenotype.
Authors: Wang Liping , Sante Gabriele Di , Wang Chenguang , Powell Michael J. , McBurney Michael W. , Pestell Richard G. 
Published: August 2014

Abstract
SIRT1 is a type III histone deacetylase, linked to diverse functions in a variety of physiological settings. SIRT1 is highly expressed in gonadogenesis and Sirt1−/− mice demonstrate infertility and die post-natally from a variety of abnormalities, including pancreas, lung, skeletal, and heart defects. Recent studies have shown reduced intratesticular testosterone levels in Sirt1−/− mice. The normal migration of GnRH neurons from the vomeronasal organ (VNO) to hypothalamus is required for their destined location where GnRH stimulates the anterior pituitary to secrete gonadotropins. A subset of genes has been found to be involved in this process. In the current studies, we investigated the function of the hypothalamic pituitary gonadal axis in Sirt1−/− mice. Herein, a GnRH stimulation test was conducted on Sirt1−/− mice or littermate controls. The addition of GnRH to Sirt1−/− mice resulted in an increase in testosterone, LH and FSH levels, to a level similar to physiological secretion in normal controls. Immunostaining of mouse E14.5 brain in sagittal sections demonstrated that most of the GnRH positive neurons migrated to the forebrain in Sirt1+/+ mice whereas in Sirt1−/- mice, all of GnRH neurons resided in the VNO region and are undetectable in the forebrain. Treatment of hypothalamic neuronal cell lines, GN11 cells or GT1-7 cells with either Sirtinol or Nicotinamide, reduced cell migration in wound-healing and Matrigel invasion assays, most dramatically in trans-well migration assays. Retroviral gene transduction of cells with an expression vector encoding SIRT1, enhanced wound closure and invasiveness while transduction with the SIRT1 H363Y mutant abrogated migration. Cortactin is an F-actin binding protein involved in cancer cell migration and neurite outgrowth. Immunoprecipitation of FLAG-tagged SIRT1 and subsequent Western blot analysis revealed the association of SIRT1 with cortactin. Inhibition of SIRT1 activity by trichostatin A (TSA) or Nicotinamide, increased cortactin acetylation in 3T3 Sirt1+/+ cells, while in 3T3 Sirt1−/− cells, Nicotinamide did not increase cortactin acetylation. Deacetylation of cortactin by SIRT1 may play a role in GnRH neuronal migration. These studies demonstrated the critical role of SIRT1 activity in GnRH neuron migration and invasion both in cultured cells and in vivo.
Citation Format: Liping Wang, Gabriele Di Sante, Chenguang Wang, Michael J. Powell, Michael W. McBurney, Richard G. Pestell. SIRT1 governs GnRH neuron migration and The Kallmann syndrome phenotype. [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 LB-266. doi:10.1158/1538-7445.AM2013-LB-266