The ability to adhere to each other is one of the most fundamental cellular functions necessary for the formation of all metazoans. The most significant histological manifestation of epithelial tumor is the focal loss of normal tissue architecture. Maintenance of normal tissue organization is one of the primary functions of cell-cell adhesion structures and intercellular adhesion is often abnormal in epithelial cancer. Our laboratory is concentrating on understanding the normal and pathological function of cell-cell adhesion protein alphaE(epithelial)-catenin. AlphaE-catenin is often downregulated in a variety of human epithelial tumors: however, the significance of this downregulation and overall mechanisms of alpha-catenin in tissue homeostasis and cancer is not well understood. To understand the significance of alpha-catenin downregulation in human cancer, we model these events in mice using conditional gene knockout technology. These and other approaches resulted in realization that alpha-catenin plays an important role in regulation of self-renewal an differentiation of stem cells and the genetic loss of alpha-catenin in stem cell compartment can result in prominent defects in tissue homeostasis and development of cancer. In this proposal we will study the molecular mechanisms of alpha-catenin in signal transduction and use genetic loss-of-function and pharmacological inhibition experiments to explore the novel therapeutic interventions for the treatment of epithelial tumors displaying a decrease or loss of alpha-catenin expression.

Public Health Relevance

Studies described in this project will help to understand the molecular mechanisms of tumor-suppressor function of alpha-catenin. We will use this knowledge to test novel targeted therapeutic interventions for the treatment of squamous cell carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA179914-01A1
Application #
8643463
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$435,521
Indirect Cost
$185,521
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109