Eppley Institute for Research in Cancer and Allied Diseases

About: Eppley Institute for Research in Cancer and Allied Diseases is a based out in . It is known for research contribution in the topics: Pancreatic cancer & Cancer. The organization has 965 authors who have published 1396 publications receiving 58994 citations.

Systems biology provides new insights into the molecular mechanisms that control the fate of embryonic stem cells.

Abstract: During the last 5 years there has been enormous progress in developing a deeper understanding of the molecular mechanisms that control the self-renewal and pluripotency of embryonic stem cells (ESC). Early progress resulted from studying individual transcription factors and signaling pathways. Unexpectedly, these studies demonstrated that small changes in the levels of master regulators, such as Oct4 and Sox2, promote the differentiation of ESC. More recently, impressive progress has been made using technologies that provide a global view of the signaling pathways and the gene regulatory networks that control the fate of ESC. This review provides an overview of the progress made using several different high-throughput technologies and focuses on proteomic studies, which provide the first glimpse of the protein-protein interaction networks used by ESC. The latter studies indicate that transcription factors required for the self-renewal of ESC are part of a large, highly integrated protein-protein interaction landscape, which helps explain why the levels of master regulators need to be regulated precisely in ESC.

Prevalence of BER gene polymorphisms in sporadic breast cancer.

Abstract: Studies suggest that breast cancer is initiated by the induction of somatic mutations from errors in the base excision repair (BER) of endogenous estrogen-induced abasic sites. If so, the inheritance of certain polymorphic mutations in BER genes involved in the incorporation and management of such errors should increase the risk of breast cancer. To test this hypothesis, we examined breast tissues from 48 women (controls, histopathologically normal tissue from reduction mammoplasty) and 40 women with breast cancer (breast tumor-adjacent, histopathologically normal tissues) for the presence of reported polymorphic mutations in four BER genes. The breast tissues were obtained from the Cooperative Human Tissue Network-western division and from the University of Nebraska Medical Center. Using PCR-RFLP procedures, the XRCC1 gene was examined for Arg194Trp and Arg399Gln, APE1 for Asp148Glu, LIG3alpha for Arg780His and PARP1 for Pro377Ser mutations. The women in this study carried only the XRCC1 Arg399Gln polymorphism. This result was surprising because APE1 148Glu was reported to be frequently inherited (allele frequency, 0.47-0.495) by USA and European women. Thus, the USA women in our study are genetically different from those in the previous studies. Among the control women, 21 (43.75%) were Arg/Arg wild-types, 20 (41.67%) were Arg/Gln heterozygotes and 7 (14.6%) were Gln/Gln homozygotes. Among the breast cancer cases, 11 (27.5%) were Arg/Arg wild-types, 16 (40%) were Arg/Gln heterozygotes and 13 (32.5%) were Gln/Gln homozygotes. Thus, the Gln allele was significantly more frequent in breast cancer cases (allele frequency, 0.52) than in controls (allele frequency, 0.35), suggesting that XRCC1 399Gln may enhance the risk of breast cancer.

Ron Knockdown and Ron Monoclonal Antibody IMC-RON8 Sensitize Pancreatic Cancer to Histone Deacetylase Inhibitors (HDACi)

Abstract: Recepteur d’origine nantais (Ron) is overexpressed in a panel of pancreatic cancer cells and tissue samples from pancreatic cancer patients. Ron can be activated by its ligand macrophage stimulating protein (MSP), thereby activating oncogenic signaling pathways. Crosstalk between Ron and EGFR, c-Met, or IGF-1R may provide a mechanism underlying drug resistance. Thus, targeting Ron may represent a novel therapeutic strategy. IMC-RON8 is the first Ron monoclonal antibody (mAb) entering clinical trial for targeting Ron overexpression. Our studies show IMC-RON8 downmodulated Ron expression in pancreatic cancer cells and significantly blocked MSP-stimulated Ron activation, downstream Akt and ERK phosphorylation, and survivin mRNA expression. IMC-RON8 hindered MSP-induced cell migration and reduced cell transformation. Histone deacetylase inhibitors (HDACi) are reported to target expression of various genes through modification of nucleosome histones and non-histone proteins. Our work shows HDACi TSA and Panobinostat (PS) decreased Ron mRNA and protein expression in pancreatic cancer cells. PS also reduced downstream signaling of pAkt, survivin, and XIAP, as well as enhanced cell apoptosis. Interestingly, PS reduced colony formation in Ron knockdown cells to a greater extent than Ron scramble control cells in colony formation and soft agarose assays. IMC-RON8 could also sensitize pancreatic cancer cells to PS, as reflected by reduced colony numbers and size in combination treatment with IMC-RON8 and PS compared to single treatment alone. The co-treatment further reduced Ron expression and pAkt, and increased PARP cleavage compared to either treatment alone. This study suggests the potential for a novel combination approach which may ultimately be of value in treatment of pancreatic cancer.

Cryptic promoter activity within the backbone of a plasmid commonly used to prepare promoter/reporter gene constructs

Abstract: This report demonstrates that the plasmids, pBLCAT2 and pBLCAT3, which are used widely for the preparation of promoter reporter gene constructs, exhibit cryptic promoter activity when expressed in embryonal carcinoma (EC) cells and their differentiated cells. The promoterless plasmid pBLCAT3 is used widely because it has two multiple cloning sites. We demonstrate that the activity of the cryptic promoter present in pBLCAT3 is increased dramatically by an enhancerlike region of the murine k-FGF gene. However, the basal cryptic promoter activity and the enhanced cryptic promoter activity can be silenced effectively by the insertion of three tandemly arranged polyadenylation sequences. To characterize the influence of the cryptic promoter in pBLCAT3, we tested its effects on two promoters. Our findings suggest that the cryptic promoter increases by several fold the expression of the reporter gene in pBLCAT2, which contains the thymidine kinase promoter. In contrast, the cryptic promoter present in pBLCAT3 does not seem to influence the expression of the k-FGF promoter. Last, we observed cryptic promoter activity when pBLCAT3 was expressed transiently in EC-differentiated cells. Together, our findings argue that transcription silencing sequences should be used when examining weak promoters in these plasmids, especially in combination with enhancers.