Ets2 is one member of the Ets transcription factor family that is essential for mouse development because of a key role in trophoblast stem cells. Ets2 functions in the stromal to support mammary tumors and additionally functions in macrophages and endothelial cells. It is activated by growth factor signaling pathways and contributes to the regulation of Cdx2, a homeobox regulator of both trophoblast and intestinal development. Ets2 has been proposed to be responsible for a repressive role of increased copies of the mouse equivalent of human chromosome 21 on experimental intestinal tumors. Our preliminary results indicate that Ets2 deficiency results in preferential colonization of colonic crypts and an increased rate of crypt fusion. We propose to determine if Ets2 restricts intestinal stem cells and tumor stem cells by inactivating Ets2 genetically and over expressing Ets2 in mice. Loss of function experiments will be performed with conditional alleles of Ets2 and intestinal stem cell specific expression of Cre recombinase. Gain of function experiments will utilize conditional expression of a new transgene driven by the keratin 18 gene and Cre recombinase expressed in intestinal stem cells. These experiments will test the hypothesis that Ets2 decreases sensitivity to intestinal tumors by regulating normal and tumor intestinal stem cells.

Public Health Relevance

If colorectal cancer is a stem cell driven disease, therapeutic strategies to instruct cancer stem cells to differentiate to a benign fate are possible. Understanding the regulation of intestinal stem cells is fundamentally important for evaluating the risk of colon cancer formation and for identifying new strategies for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK092084-03
Application #
8306961
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Carrington, Jill L
Project Start
2010-09-30
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$419,884
Indirect Cost
$204,559
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Munera, Jorge; Cecena, Grace; Jedlicka, Paul et al. (2011) Ets2 regulates colonic stem cells and sensitivity to tumorigenesis. Stem Cells 29:430-9