Historically, research has focused on the ability of ionizing radiation (IR) to eradicate the tumor by eliminating cancer cells through DNA damage and apoptosis. However, as we have pointed out in a recent review, the global consequences of IR on the normal tissue microenvironment can also have important clinical implications. Extracellular matrix (ECM) has been shown to mediate signaling through its receptors such as ?1 integrin and is critical to maintenance of normal tissue structure, a feature that is fundamentally disrupted in the malignant phenotype. ??1 integrin signaling has been implicated in breast cancer progression, and, in addition, has been shown to facilitate resistance to chemotherapy and IR in several human cancers. We have shown previously that ?1 integrin expression is aberrantly up regulated after IR exposure in a heritable and persistent manner in mammary epithelial cells cultured in a 3-dimensional laminin rich matrix (3D lrECM). My initial studies have shown that ?1 integrin inhibition resulted in enhanced apoptosis and decreased proliferation among breast cancer cell lines in the 3D lrECM culture model and in vivo with no discernible toxicity to animals. Importantly, in a study of early stage invasive breast cancer patients, we found that increased ?1 integrin expression was prognostic for recurrence-free and overall survival at 5 and 10 years (Appendix IV). In the present proposal, our preliminary data demonstrates that ?1 integrin inhibition enhances the therapeutic efficacy of IR in 3DlrECM and in vivo; these promising findings have the potential to impact clinical RT for patients. We hypothesize that ?1 integrin mediates a pro-survival signal after IR via Akt that can be targeted for therapy. The primary focus of this proposal therefore will be to investigate if IR induced ?1 integrin signaling mediates a survival signal via Akt using 3D lrECM culture models of invasive breast cancer and ductal carcinoma in situ (DCIS) and to expand upon the Akt-mediated survival effects of ?1 integrin signaling post-IR in the context of the tumor microenvironment in vivo. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA124891-01A2
Application #
7389180
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
2008-04-04
Project End
2013-01-31
Budget Start
2008-04-04
Budget End
2009-01-31
Support Year
1
Fiscal Year
2008
Total Cost
$391,754
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Biology
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
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