1987 |
Dewille, James W |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Thymidylate Synthase Transcriptional Control Sequences |
0.958 |
1991 |
Dewille, James W |
S15Activity Code Description: Undocumented code - click on the grant title for more information. |
Small Instrumentation Grant
biomedical equipment purchase;
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0.958 |
1994 — 1999 |
Dewille, James W |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
C/Ebp Isoform Expression in Mammary Gland and Tumors
Breast cancer is the number one form of cancer and the second leading cause of cancer deaths among US women (18). Of the known breast cancer risk factors (age, sex, family history, diet), only diet may be controllable (11). The "dietary fat/breast cancer" hypothesis, however, is controversial (22). Despite this controversy national health agencies recommend a reduction in fat intake to reduce breast cancer risk and clinical trials with very low fat diets are in progress with high risk women and breast cancer patients (28). In addition, the historic Women's Health Initiative will soon test the "dietary fat/breast cancer" hypothesis with a 10 year study enrolling 70,000 women (16,26). Much of the controversy over the role of dietary fat in breast cancer stems from the lack of a biochemical mechanism linking fat and tumor promotion. CCAAT/Enhancer binding proteins (C/EBPs) are transcription factors implicated in the regulation of genes involved in growth control, differentiation and energy metabolism (1-15). These unique properties have led to speculation that C/EBP isoforms may play a general role be tumorigenesis and may play a specific role as a link between dietary fat and mammary tumor promotion. Mammary gland expresses a unique pattern of C/EBP isoforms suggesting important functions for C/EBPs in normal mammary gland biology. This proposal will investigate the expression of C/EBP isoforms during mammary gland proliferation and assess the potential role of C/EBPs in mammary tumor promotion by dietary fat. Three specific objectives are proposed. (1) Investigate C/EBP isoform mRNA levels during three principal proliferative phases in normal mouse mammary gland development: embryonic, sexual maturation and during pregnancy/lactation. (2) Investigate the influence of varying corn oil (CO) intake [5, 12.5 and 25% CO (by calorie)] on mammary gland C/EBP isoform expression in normal mouse mammary gland and in mammary tumors developed in transgenic mice (MMTV/c-neu) (51). (3) Investigate the influence of proliferation and differentiation of mammary cells on C/EBP phosphorylation and nuclear localization. Current public health information regarding breast cancer is limited to encouraging early detection of existing disease. It is imperative that we investigate the regulation of genes, such as C/EBPs, that are implicated in mammary cell growth control, differentiation and possibly tumorigenesis. In addition, C/EBP isoforms may provide a biochemical link between dietary fat and mammary tumorigenesis. Understanding this link could lead to the implementation of effective preventative measures to reduce breast cancer risk.
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0.958 |
1999 — 2003 |
Dewille, James W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
C/Ebp Delta Controls Mammary Epith Cell G Growth Arrest
The broad, long term objective of this research is to investigate the mechanism by which mammary epithelial cells initiate and maintain G0 growth arrest. The specific aims will investigate the regulation and function of C/EBPdelta, a transcription factor that is highly induced in mammary epithelial cells during G0 growth arrest and prior to the onset of apoptosis. The hypothesis is that C/EBPdelta regulates mammary epithelial cell G0 growth arrest. Loss of C/EBPdelta alters growth control and predisposes to mammary tumorigenesis. The specific aims are: 1) Investigate the transcriptional regulation of C/EBPdelta gene expression in mammary epithelial cells, 2) Investigate the intracellular signal transduction pathway that activates C/EBPdelta gene expression in mammary epithelial cells, 3) Investigate the posttranscriptional regulation of C/EBPdelta in mammary epithelial cells, 4) Investigate the role of C/EBPdelta in mammary gland development, programmed cell death and tumorigenesis in vivo in C/EBPdelta knockout mice. The health-relatedness of this project is that it fills gaps in our knowledge about G0 growth regulation in mammary epithelial cells, the principal cell population implicated in human breast cancer. Few G0 genes have been identified and little is known about their regulation. The experimental design will utilize a well-characterized mammary epithelial cell line (HC11) to investigate the role of extracellular ligands, intracellular signal transduction pathways and transcriptional and posttranscriptional control mechanisms in C/EBPdelta regulation. C/EBPdelta knockout mice will be used to address the physiological relevance of C/EBPdelta in mammary gland biology in vivo. The methodology will use transfection of C/EBPdelta promoter-reporter and indicator transcript constructs to investigate transcriptional and posttranscriptional regulation. Specific DNA-protein interactions are assessed by band shift and antibody interference assays. Gene expression is evaluated by northern and western blot. In vivo analysis of C/EBPdelta regulation and function will use tissue morphology, in situ labelling, tumor detection and characterization methods. The results will provide a better understanding of G0 growth arrest in mammary epithelial cells and new insights into the etiology, progression and possibly treatment of breast cancer.
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0.958 |
2004 — 2007 |
Dewille, James W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
C/Ebpdelta Controls Mammary Cell G0 Growth Arrest
DESCRIPTION (provided by applicant): The boad, long term objective of this research is to investigate the molecular mechanisms underlying the broad, long term objective regulation and function of CCAAT/Enhancer Bin,clingProteindelta(C/EBPdelta), a member of the C/EBP family of nuclear proteins. Although experimental studies demonstrate that C/EBPdelta functions as a growth suppressor and clinical breast cancer studies correlate reduced C/EBPdelta levels with a poor prognosis, regulation and function of C/EBPdelta is incompletely understood. The specific aims of this proposal are: (1) investigate the role of specific transcription factors, co-activators, methyl-CpG binding proteins and chromatin remodeling complex components in the transcriptional activation of the C/EBPdelta gone; (2) investigate and identify proteins, protein modifications and protein degradation complexes that mediate C/EBPdelta post transcriptional and post translational regulation; (3) investigate the functional significance of C/EBPdelta interactions with key cell cycle regulatory proteins (Rb, E2F1 and p27); (4) investigate the transcriptional activator role of C/EBPdelta in growth control by identifying and characterizing C/EBPdelta regulated genes. The experimental techniques include protein/protein interaction assays, gene expression analyses and an innovative "CHIP on CHIP" assay. Our overall hypothesis is that C/EBPdelta plays a key role in cell growth control and that "loss of function" alterations in the C/EBPdelta gene promote neoplastic development. The health-relatedness of this research project lies in the novel growth suppressor function of C/EBPdelta, which is specific to the initiation and maintenance of GO growth arrest. Few GO genes have been identified and little is known about the regulation of GO. The proposed studies will provide a better understanding of the regulation and function of C/EBPdelta, and in doing so; provide a working model for other G0-specific genes and their potential role in tumorigenesis.
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0.958 |