Mechanisms Regulating Reversal of Malignancy

Summary

Principal Investigator: Priscilla Furth
Abstract: Our long-range goal is to establish the mechanisms underlying successful therapeutic approaches to reverse preneoplasia, identify genetic and molecular events that impair reversal, identify predictive biomarkers and translate results to people. This Project will exploit unique conditional mouse models of breast and salivary gland cancer to define the role of p53 in pharmacological differentiation therapies that target nuclear receptors Retinoid X Receptor alpha (RXRalpha) and Peroxisome proliferator-activated receptor gamma (PPARgamma). 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. The central hypothesis of this proposal is that ligand induced activation of RXRalpha and PPARgamma in epithelial cells can impel resolution of refractory dysplasia through a re-differentiation process that involves down-regulation of Protein Phosphatase 2A (PP2A) activity. A secondary hypothesis is that normal p53 function contributes to the re-differentiation process initiated by RXRalpha and/or PPARgamma agonists. Hypothesis: The mechanism by which pharmacological activation of RXRalpha and/or PPARgamma in epithelial cell preneoplasia in vivo leads to successful disease reversal is through cell cycle arrest and differentiation mediated by down- regulation of PP2Ac, DP-1 phosphorylation, decreased CDK-2, increased p27, increased p53 activity, and decreased collagen production with changes in the extracelllalr matrix. Additional mechanisms that will be activated in ERalpha positive mammary preneoplasia include down-regulation of ERalpha and cyclin D1, up- regulation of Brca1 and decreased collagen production with changes in the extracellular matrix. Specific Aims: 1. a. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination are able to redifferentiate refractory dysplastic salivary tissue in GRIDS mice through down-regulation of PP2Ac expression with secondary gain of DP-1 phosphorylation, loss of CDK-2, and increased p27 expression. 1. b. Test if normal p53 expression levels contribute to successful reversal by these pharmacological agents. 2. a. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination redifferentiate ERalpha-expressing ductal hyperplasia and DCIS in CERM mice through down-regulation of PP2Ac, gain of DP-1 phosphorylation, increased p27 and loss of CDK-2 and/or through loss of ERalpha, cyclin D1 and increased Brca1. Compare histological and molecular responses to the RXRalpha and/or PPARgamma agonists with the ERalpha antagonist tamoxifen and conditional down-regulation of the ERalpha transgene. 2. b. Test if normal p53 expression contributes to successful reversal by pharmacological RXR and/or PPARgamma agonists, the ERalpha antagonist tamoxifen and/or conditional down-regulation of the ERalpha transgene. 2. c. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination prevent development of ERalpha ductal hyperplasia and DCIS.
Funding Period: 2009-08-01 - 2011-07-31
more information: NIH RePORT

Top Publications

  1. pmc Cancer prevention as biomodulation: targeting the initiating stimulus and secondary adaptations
    Priscilla A Furth
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    Ann N Y Acad Sci 1271:1-9. 2012
  2. pmc Assessing estrogen signaling aberrations in breast cancer risk using genetically engineered mouse models
    Priscilla A Furth
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    Ann N Y Acad Sci 1229:147-55. 2011
  3. pmc BRCA1 deficient mouse models to study pathogenesis and therapy of triple negative breast cancer
    Edgar S Diaz-Cruz
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
    Breast Dis 32:85-97. 2010
  4. pmc Functional mimicry of the acetylated C-terminal tail of p53 by a SUMO-1 acetylated domain, SAD
    Amrita Cheema
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA
    J Cell Physiol 225:371-84. 2010
  5. pmc The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway
    M Carla Cabrera
    Department of Oncology, Georgetown University, Washington, DC 20057, USA
    Cancer Prev Res (Phila) 5:810-21. 2012
  6. pmc Comparison of mouse mammary gland imaging techniques and applications: reflectance confocal microscopy, GFP imaging, and ultrasound
    Maddalena T Tilli
    Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
    BMC Cancer 8:21. 2008
  7. ncbi Effects of ERalpha overexpression on female reproduction in mice
    Dragana Tomic
    Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
    Reprod Toxicol 23:317-25. 2007
  8. ncbi What do shifts in indicators of apoptosis indicate about the cancer process?
    Priscilla A Furth
    Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC 20057, USA
    J Nutr 136:2700S-3S. 2006
  9. ncbi Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice
    Dragana Tomic
    Program in Toxicology, Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore, Maryland 21201, USA
    Toxicol Sci 93:196-204. 2006
  10. ncbi Deregulated estrogen receptor alpha expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in situ
    M Silvina Frech
    Lombardi Comprehensive Cancer Center, Departments of Oncology and Pathology, Georgetown University, 3970 Reservoir Road, Washington, DC 20057, USA
    Cancer Res 65:681-5. 2005

Scientific Experts

  • Priscilla Furth
  • Maddalena T Tilli
  • Dragana Tomic
  • Edgar S Diaz-Cruz
  • Jodi A Flaws
  • M Carla Cabrera
  • Amrita Cheema
  • Robert D Koos
  • Maria Silvina Frech
  • Janice K Babus
  • M Silvina Frech
  • Michael J Pishvaian
  • Bhaskar V S Kallakury
  • Clinton J Grubbs
  • Donald D Muccio
  • Rebecca Nakles
  • Beth H Rutstein
  • Ricardo Perez
  • Maria Laura Avantaggiati
  • Christopher Albanese
  • Chad D Knights
  • Sivanesan Dakshanamurthy
  • Vamsi K Kolukula
  • Brigitte Simons
  • Marina C Cabrera
  • Jason Catania
  • Mahadev Rao
  • Daniel Symonds
  • Rupesh K Gupta
  • Baljit Singh
  • Edward J Gunther
  • Ewa D Halama
  • Lewis A Chodosh

Detail Information

Publications11

  1. pmc Cancer prevention as biomodulation: targeting the initiating stimulus and secondary adaptations
    Priscilla A Furth
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    Ann N Y Acad Sci 1271:1-9. 2012
    ..Characterization of these accommodating adaptations could provide insight for the development of cancer preventive regimens that might more effectively biomodulate preneoplastic cells toward a more normal state...
  2. pmc Assessing estrogen signaling aberrations in breast cancer risk using genetically engineered mouse models
    Priscilla A Furth
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    Ann N Y Acad Sci 1229:147-55. 2011
    ..Loss of breast cancer gene 1 increases estrogen signaling and cooperates with ERĪ± overexpression in initiation, promotion, and progression of mammary cancer...
  3. pmc BRCA1 deficient mouse models to study pathogenesis and therapy of triple negative breast cancer
    Edgar S Diaz-Cruz
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
    Breast Dis 32:85-97. 2010
    ..Examples of the use of genetically engineered, allograft and xenografts models for preventive and therapeutic studies are presented...
  4. pmc Functional mimicry of the acetylated C-terminal tail of p53 by a SUMO-1 acetylated domain, SAD
    Amrita Cheema
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA
    J Cell Physiol 225:371-84. 2010
    ..Further, they imply that the pleiotropy of effects by which SUMO-1 influences various cellular outcomes and the activity of p53 depends upon its acetylation state...
  5. pmc The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway
    M Carla Cabrera
    Department of Oncology, Georgetown University, Washington, DC 20057, USA
    Cancer Prev Res (Phila) 5:810-21. 2012
    ..In summary, the study distinguished CDK4 and phosphorylated pRb as targets for chemoprevention regimens targeting reversal of hyperplasia and dysplasia...
  6. pmc Comparison of mouse mammary gland imaging techniques and applications: reflectance confocal microscopy, GFP imaging, and ultrasound
    Maddalena T Tilli
    Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
    BMC Cancer 8:21. 2008
    ..However, traditional whole mount and histological imaging modalities are only applicable to non-viable tissue...
  7. ncbi Effects of ERalpha overexpression on female reproduction in mice
    Dragana Tomic
    Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
    Reprod Toxicol 23:317-25. 2007
    ....
  8. ncbi What do shifts in indicators of apoptosis indicate about the cancer process?
    Priscilla A Furth
    Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC 20057, USA
    J Nutr 136:2700S-3S. 2006
  9. ncbi Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice
    Dragana Tomic
    Program in Toxicology, Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore, Maryland 21201, USA
    Toxicol Sci 93:196-204. 2006
    ..The trend toward greater sensitivity to MXC in ERalpha-overexpressing mice compared to control animals cannot be explained by alterations in estradiol and/or FSH levels...
  10. ncbi Deregulated estrogen receptor alpha expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in situ
    M Silvina Frech
    Lombardi Comprehensive Cancer Center, Departments of Oncology and Pathology, Georgetown University, 3970 Reservoir Road, Washington, DC 20057, USA
    Cancer Res 65:681-5. 2005
    ....