This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of this proposal is to determine the effect of L1 expression in human mammary cells in tissue culture and mammary glands of the mouse model of human breast cancer on malignant transformation, tumor growth and metastatic development. The proposal is set up to evaluate L1-associated mutation rate in mammary gland and whether this rate changes in cancer. These goals are biologically relevant because the existing data indicate that L1-induced DNA damage in the form of double-strand breaks (DSBs) is potentially much greater than the insult to the genome caused by the element via insertional mutagenesis. We detected endogenous L1 expression in a number of somatic cells and it is reported to be significantly upregulated in the majority of malignancies. Thus, L1-associated DNA damage has consequences for the whole organism, not only for its progeny. Normal and non-metastatic breast cancer cells will be exposed to ongoing L1 expression and used to test their growth properties and ability to form tumors and metastasis in the mouse model. A mouse model of human breast cancer will be used to test the effect of L1 expression on the mammary tumor onset, growth, and metastasis in vivo. The same model will be used to determine the rate and spectrum of the L1-induced DNA damage in mammary gland. Reported ability of L1 elements to inflict DNA damage and its endogenous expression in a number of human tissues fundamentally changes our understanding of the significance of the L1 expression and its health impact. This project is designed to determine whether ongoing L1 expression in somatic cells leads to a steady accumulation of mutations due to the error-prone repair of the DSBs created by the L1 endonuclease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR020152-08
Application #
8360722
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
2011-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$269,200
Indirect Cost
Name
Tulane University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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