NSAID use is associated with decreased breast cancer recurrence. Using pre-clinical models we have shown that NSAIDs, which are selective and non-selective inhibitors of COX-2, can reduce postpartum breast tumor associated lymphangiogenesis, invasion, and metastasis. Given that lymph node metastasis, invasion of tumor cells into peritumor lymphatic vessels, and increased lymphatic vessel density (LVD) in the peritumor region correlate with increased metastasis in a number of human cancers including breast, new lymphatic vessel formation likely plays a key role in tumor cell dissemination. However, very little is known about the mechanisms of tumor induced lymphangiogenesis that may drive tumor metastasis. We have identified a developmental window of mammary gland development that promotes mammary tumor metastasis and is characterized by COX-2 dependent lymphangiogenesis. The proposed aims will identify mechanisms underlying COX-2 dependent lymphangiogenesis in the mammary gland, which may promote increased metastasis of young women's breast cancers.
Specific Aim 1 : Will determine the relationship between COX-2, VEGF-C, and Sem7a in pre-clinical models of breast tumor cell lymphogenous spread.
Specific Aim 2 : Will analyze the contribution of COX-2/VEGF-C/Sem7a signaling to young women's breast cancer through investigation of protein and mRNA expression of lymphatic vessel markers, COX-2, VEGF-C, and Sem7a in our young women's cohorts and in patient derived xenografts. Mechanisms uncovered by these aims will expand our understanding of how COX-2 inhibitors, NSAIDs, may improve survival rates for young women with breast cancer.

Public Health Relevance

We will test the hypothesis COX-2 mediates lymphangiogenesis in the pre-menopausal breast cancer via VEGF-C and Sem7a. Mechanisms uncovered by our studies will provide impetus for clinical trials with NSAIDs aimed at improving prognosis of thousands of breast cancer patients annually.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA185226-01
Application #
8687473
Study Section
Special Emphasis Panel (ZCA1-RTRB-L (J1))
Program Officer
Jhappan, Chamelli
Project Start
2014-06-03
Project End
2016-05-31
Budget Start
2014-06-03
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$202,221
Indirect Cost
$71,721
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045