Matrix metalloproteinases (MMPs) are essential for many physiological processes, but inappropriate expression of MMPs can facilitate the development and progression of tumors. Recognition of the relationship between MMPs and malignancy led to clinical trials of broad-spectrum MMP inhibitors as cancer therapeutics, but the results were disappointing. The failure of the clinical trials was due in large part to the propensity of the MMP inhibitors to inhibit essential physiological processes. Therapeutic strategies that target tumor-specific MMP-dependent effects may prove more promising. Previous studies and our preliminary data show that exposure of mammary epithelial cells to selected MMPs causes cleavage of a cell surface molecule that stimulates cellular production of reactive oxygen species (ROS). MMP-dependent production of ROS causes cells to undergo epithelial-mesenchymal transition (EMT), a fundamental phenotypic alteration associated with progression to metastasis, and compromises the cellular genomic stability. Our long-term objective is to identify the specific steps associated with the MMP-induced malignant transformation so as to determine potential points for therapeutic intervention. To do this, we propose (1) to identify the proteolytic target of MMPs that stimulates the development of ROS, (2) to determine roles of transcription factors Snail and Twist in MMP/ROS-induction of EMT, and (3) to define how MMP/ROS stimulate genomic instability.
In Aim 1, investigations of the specific role of cleavage of E-cadherin by MMPs will be supplemented by a proteolytic screen for additional/alternative targets.
In Aim 2, we will identify the MMP-induced factors responsible for the increased expression of Snail and Twist, and will dissect the relative role of these transcription factors on the MMP-induced EMT.
In Aim 3, we will examine how MMP/ROS induce cellular aneuploidy and mitotic abnormalities through stimulation of centrosome amplification. We expect that by elucidating the chain of events in the induction of EMT and genomic instability by MMPs, we will be able to identify novel promising points for therapeutic intervention in breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122086-03
Application #
7666046
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2007-09-01
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$286,900
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
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