Our major long-term goal is to develop strategies for the prevention and treatment of breast cancer through translational research. Cyclooxygenase-2 (COX-2) overexpression plays a key role in tumorigenesis by stimulating epithelial cell proliferation, inhibiting apoptosis, stimulating angiogenesis, and enhancing cell invasiveness. Studies using mouse models of colon cancer, and the results of clinical trials have shown COX-2 to be a useful target for the prevention and treatment of colon cancer. Studies in other epithelial cancers at different organ sites, including breast, prostate, bladder, lung, and pancreas, suggest that COX-2 plays an important role in the pathogenesis of these cancers. Little is known about the specific role of COX-2 in human breast cancer, and even less so in case of tumor metastasis to the bone. Our plan is to test the hypothesis that increased production of COX-2 in the breast cancer cells is responsible for initiating a series of events that facilitate the spread of breast cancer to the bone. We hypothesize that COX-2- mediated production of prostaglandin E2 (PGE2) by breast cancer cells results in activation of urokinase-type plasminogen activator (uPA), causing the destruction of surrounding tissues and allowing invasion of tumor cells. There is evidence in epithelial cancers that PGE2 induces uPA expression in both tumor cells and surrounding tissues. Clinical studies have documented that high levels of uPA predict a worse outcome from breast cancer. PGE2 is known to cause the activation of bone remodeling cells, called osteoclasts, to induce bone breakdown, the first step in metastasis to bone. When bone is broken down by osteoclasts, growth factors are released into the surrounding tissue, helping tumor cells to grow and spread at their new site.
Specific Aims of this project are: 1) to demonstrate that breast cancer cell lines known to metastasize to bone overexpress COX-2, PGE2, and uPA thus allowing the cancer cells to invade the extracellular matrix and to stimulate osteoclast-mediated bone resorption, and to demonstrate that COX-2 inhibitors can block these processes, 2) to demonstrate that overexpression of COX-2 is a key step in establishing bone metastases in a nude mouse model and that a COX-2 inhibitor can block metastasis to the bone, and 3) to demonstrate that primary human breast cancers that metastasize to the bone produce increased levels of COX-2 as compared to breast cancers that do not metastasize to the bone. The experiments in our proposed study will show that specific inhibitors of COX-2 enzyme prevent formation of bone metastases from breast cancer. The data gathered from our proposed study is the important first step in developing clinical trials for the chemoprevention and treatment of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK067682-01
Application #
6687138
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (M2))
Program Officer
Malozowski, Saul N
Project Start
2003-09-15
Project End
2004-08-31
Budget Start
2003-09-15
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$150,500
Indirect Cost
Name
Baylor College of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Gainer, Sarah M; Lodhi, Ashutosh K; Bhattacharyya, Anirban et al. (2012) Invasive lobular carcinoma predicts micrometastasis in breast cancer. J Surg Res 177:93-6
Singh, Balraj; Cook, Kendra R; Vincent, Laura et al. (2011) Role of COX-2 in tumorospheres derived from a breast cancer cell line. J Surg Res 168:e39-49
Singh, Balraj; Cook, Kendra R; Martin, Cecilia et al. (2010) Evaluation of a CXCR4 antagonist in a xenograft mouse model of inflammatory breast cancer. Clin Exp Metastasis 27:233-40
Singh, Balraj; Irving, LaTashia R; Tai, Karen et al. (2010) Overexpression of COX-2 in celecoxib-resistant breast cancer cell lines. J Surg Res 163:235-43
Lang, Julie E; Mosalpuria, Kailash; Cristofanilli, Massimo et al. (2009) HER2 status predicts the presence of circulating tumor cells in patients with operable breast cancer. Breast Cancer Res Treat 113:501-7
Huang, Eugene H; Singh, Balraj; Cristofanilli, Massimo et al. (2009) A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J Surg Res 155:231-6
Lucci, Anthony; Krishnamurthy, Savitri; Singh, Balraj et al. (2009) Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow. Breast Cancer Res Treat 117:61-8
Singh, Balraj; Cook, Kendra R; Vincent, Laura et al. (2008) Cyclooxygenase-2 induces genomic instability, BCL2 expression, doxorubicin resistance, and altered cancer-initiating cell phenotype in MCF7 breast cancer cells. J Surg Res 147:240-6
Singh, B; Berry, J A; Shoher, A et al. (2007) COX-2 involvement in breast cancer metastasis to bone. Oncogene 26:3789-96
Singh, Balraj; Vincent, Laura; Berry, Jacob A et al. (2007) Cyclooxygenase-2 expression induces genomic instability in MCF10A breast epithelial cells. J Surg Res 140:220-6

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