Long-range objective: Establish therapeutic approaches that can be used to treat preneoplastic disease. Reversal of premalignant disease is one goal of cancer prevention treatment programs. Interruption of the malignant process at an early stage is preferable to treating the fully developed, and perhaps metastatic, cancer. While inroads have been made in identifying therapeutic agents for reversal of human malignancy, investigations continue. Mechanism-based preclinical and clinical studies are utilized to identify stages of treatable premalignancy and the most appropriate genetic and cellular targets. This study will test the role of specific genetic mechanisms possibly responsible for reversal of premalignant disease utilizing a unique transgenic mouse model of cancer development. In this model temporal expression of the initiating oncoprotein (Simian Virus SV40 T Antigen (TAg)) is conditionally regulated by the tetracycline responsive gene expression (tet responsive) system and directed to epithelial cells by the mouse mammary tumor virus long terminal repeat (MMTV-LTR). When expression of the oncoprotein is terminated after four months, hyperplasia reverses. In contrast, when oncoprotein expression is terminated after seven months, no reversal of hyperplasia is found. Adenocarcinomas that can metastasize to the lung develop between nine and twelve months of age when TAg expression is not interrupted. Specific accomplishments for this proposal: 1) Establish if p53 and Bax induction are critical genetic pathways for the successful reversal of premalignant disease in the whole animal. 2) Determine why pathways that mediate reversal at an early stage of cancer progression in this model cannot promote reversal at a later stage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA089041-02
Application #
6540880
Study Section
Pathology B Study Section (PTHB)
Project Start
2000-12-15
Project End
2005-11-30
Budget Start
2001-10-26
Budget End
2001-11-30
Support Year
2
Fiscal Year
2001
Total Cost
$141,612
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Cabrera, M Carla; Tilahun, Estifanos; Nakles, Rebecca et al. (2014) Human Pancreatic Cancer-Associated Stellate Cells Remain Activated after in vivo Chemoradiation. Front Oncol 4:102
Nakles, Rebecca E; Millman, Sarah L; Cabrera, M Carla et al. (2013) Time-lapse imaging of primary preneoplastic mammary epithelial cells derived from genetically engineered mouse models of breast cancer. J Vis Exp :
Miermont, Anne M; Cabrera, Marina Carla; Frech, Silvina M et al. (2012) Association of Over-Expressed Estrogen Receptor Alpha with Development of Tamoxifen Resistant Hyperplasia and Adenocarcinomas in Genetically Engineered Mice. Anat Physiol Suppl 12:
Cabrera, M Carla; Díaz-Cruz, Edgar S; Kallakury, Bhaskar V S et al. (2012) The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway. Cancer Prev Res (Phila) 5:810-21
Furth, Priscilla A (2012) Cancer prevention as biomodulation: targeting the initiating stimulus and secondary adaptations. Ann N Y Acad Sci 1271:1-9
Furth, Priscilla A; Cabrera, M Carla; Díaz-Cruz, Edgar S et al. (2011) Assessing estrogen signaling aberrations in breast cancer risk using genetically engineered mouse models. Ann N Y Acad Sci 1229:147-55
Cheema, Amrita; Knights, Chad D; Rao, Mahadev et al. (2010) Functional mimicry of the acetylated C-terminal tail of p53 by a SUMO-1 acetylated domain, SAD. J Cell Physiol 225:371-84
Diaz-Cruz, Edgar S; Cabrera, Marina C; Nakles, Rebecca et al. (2010) BRCA1 deficient mouse models to study pathogenesis and therapy of triple negative breast cancer. Breast Dis 32:85-97
Kleinberg, David L; Wood, Teresa L; Furth, Priscilla A et al. (2009) Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions. Endocr Rev 30:51-74
Tilli, Maddalena T; Parrish, Angela R; Cotarla, Ion et al. (2008) Comparison of mouse mammary gland imaging techniques and applications: reflectance confocal microscopy, GFP imaging, and ultrasound. BMC Cancer 8:21

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