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.

Expression of the prolactin gene in normal and neoplastic human breast tissues and human mammary cell lines : Promoter usage and alternative mRNA splicing

Abstract: Prolactin (PRL) has been implicated in the development of mammary cancer in rodents and humans. Although PRL and its mRNA have been detected in breast tissues and some mammary cell lines, the role of PRL as an autocrine/paracrine growth factor within the breast is not clear. A second, more distal, promoter has recently been identified in the human PRL gene. We have used reverse transcription-polymerase chain reaction (RT-PCR) to determine whether the distal or the proximal promoter directs expression of the PRL gene in normal and neoplastic breast tissues and in mammary cell lines. Total RNA was isolated from 10 normal and 20 neoplastic breast tissue samples and from 8 mammary cell lines; MDA-MB-231, SK-BR-3, T-47D, MCF10, MCF10T2, and 3 MCF7 derivatives. The RNA was reverse transcribed to cDNA using random hexamers as primers. PCR amplification of the cDNAs was performed, using a variety of PRL-specific primer pairs, and the DNA products were subjected to agarose gel electrophoresis and Southern blotting. The resulting data indicate that the PRL gene is expressed in the majority of both normal and neoplastic breast tissue samples, as well as all of the mammary cell lines. PRL-specific PCR products corresponding to transcripts that originated from the distal promoter were observed in a subset of the normal and neoplastic breast tissue samples and mammary cell lines. Together these data indicate that PRL transcripts in human breast tissues and human mammary cell lines originate, at least in part, from the distal PRL promoter. In addition, data are presented which suggest that PRL transcripts in breast tissues and mammary cell lines may undergo alternative splicing.

Mechanism of metabolic activation of the potent carcinogen 7,12-dimethylbenz[a]anthracene

Abstract: The DNA adducts of 7,12-dimethylbenz[a]anthracene (DMBA) previously identified in vitro and in vivo are stable adducts formed by reaction of the bay-region diol epoxides of DMBA with dG and dA. In this paper we report identification of several new DMBA-DNA adducts formed by one-electron oxidation, including two adducts lost from DNA by depurination, DMBA bound at the 12-methyl to the N-7 of adenine (Ade) or guanine (Gua) [7-methylbenz[a]anthracene (MBA-12-CH2-N7Ade or 7-MBA-12-CH2-N7Gua, respectively]. The in vitro systems used to study DNA adduct formation were DMBA activated by horseradish peroxidase or 3-methyl-cholanthrene-induced rat liver microsomes. The biologically-formed depurination adducts were identified by high-pressure liquid chromatography and by fluorescence line narrowing spectroscopy. Stable DMBA-DNA adducts were analyzed by the 32P-postlabeling method. Quantitation of DMBA-DNA adducts formed by microsomes showed about 99% as depurination adducts: 7-MBA-12-CH2-N7Ade (82%) and 7-MBA-12-CH2-N7Gua (17%). Stable adducts (1.4% of total) included one adduct spot that may contain adduct(s) formed from the diol epoxide (0.2%) and unidentified adducts (1.2%). Activation of DMBA by horseradish peroxidase afforded 56% of stable unidentified adducts and 44% of depurination adducts, with 36% of 7-MBA-12-CH2-N7Ade and 8% of 7-MBA-12-CH2-N7Gua. Adducts containing the bond to the DNA base at the 7-CH3 group of DMBA were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways

Abstract: The BH3-only proteins of the Bcl-2 family are known to mediate mitochondrial dysfunction during apoptosis However, the identity of the critical BH3-only proteins and the mechanism of their action following treatment by diverse apoptotic stimuli remain to be fully resolved We therefore used RNAi to screen the entire Bcl-2 family for their involvement in three major apoptotic pathways in HeLa cells We found that Bcl-xL and Mcl-1 are major inhibitors of apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL), endoplasmic reticulum (ER) stress, and proteasome inhibition Among the 10 BH3-only proteins, Bid and Noxa were found to be critically involved in TRAIL-induced apoptosis, in which Noxa participates by constitutively binding to Mcl-1 Bim and Noxa were found to be necessary for ER stress-induced apoptosis, in which Noxa assisted Bim function by sequestering Mcl-1 and binding to Bcl-xL As a critical BH3-only protein, Noxa was strongly upregulated and became associated with both Mcl-1 and Bcl-xL during apoptosis induced by proteasome inhibition In addition, we found that Noxa became 'Mcl-1 free' following treatment by ER stress and proteasome inhibition, but not after TRAIL treatment These results defined the critical Bcl-2 network during apoptosis and suggested that Noxa participated in triggering mitochondrial dysfunction in multiple apoptotic pathways through distinct mechanisms

Phosphoinositide 3-Kinase Signaling Pathway in Pancreatic Ductal Adenocarcinoma Progression, Pathogenesis, and Therapeutics

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by its sudden manifestation, rapid progression, poor prognosis, and limited therapeutic options. Genetic alterations in key signaling pathways found in early pancreatic lesions are pivotal for the development and progression of pancreatic intraepithelial neoplastic lesions into invasive carcinomas. More than 90% of PDAC tumors harbor driver mutations in K-Ras that activate various downstream effector-signaling pathways, including the phosphoinositide-3-kinase (PI3K) pathway. The PI3K pathway also responds to stimuli from various growth factor receptors present on the cancer cell surface that, in turn, modulate downstream signaling cascades. Thus, the inositide signaling acts as a central node in the complex cellular signaling networks to impact cancer cell growth, motility, metabolism, and survival. Also, recent publications highlight the importance of PI3K signaling in stromal cells, whereby PI3K signaling modifies the tumor microenvironment to dictate disease outcome. The high incidence of mutations in the PI3K signaling cascade, accompanied by activation of parallel signaling pathways, makes PI3K a promising candidate for drug therapy. In this review, we describe the role of PI3K signaling in pancreatic cancer development and progression. We also discuss the crosstalk between PI3K and other major cellular signaling cascades, and potential therapeutic opportunities for targeting pancreatic ductal adenocarcinoma.

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

Abstract: A cluster of six microRNAs (miRNAs), miR-17-92, is processed from the transcript of C13orf25 , a gene amplified in some lymphomas and solid tumors. We find that levels of the miRNAs in the cluster do not vary entirely in parallel with each other or with the primary RNA in B-cell lines or normal cells, suggesting that processing or stability of the miRNAs is differentially regulated. Using luciferase reporter assays, we identified the region required for maximum promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually have only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. MYC is known to regulate C13orf25 ; surprisingly, mutation of a putative promoter MYC-binding site enhanced promoter activity. We found that the inhibitory MYC family member MXI1 bound to this region. The chromatin structure of a >22.5-kb region encompassing the gene contains peaks of activating histone marks, suggesting the presence of enhancers, and we confirmed that at least two regions have enhancer activity. Because the miR-17-92 cluster acts as an important oncogene in several cancers and targets genes important in regulating cell proliferation and survival, further studies of its transcriptional control are warranted.