Breast cancer is the most common cause of cancer in women and the second most common cause of cancer death in women in the United States. In 2009, approximately 40,170 women in the US are estimated to die from breast cancer. In most cases, death results from metastasis of breast cancer cells. Cancer patients with metastasis cannot currently be cured. Therefore, the invention of therapy to treat breast cancer metastasis remains a critical medical challenge. We have recently discovered increased expression of DcR3 in metastatic breast cancer. DcR3 increases have already been reported in a variety of cancers and DcR3 is well known for its tumorigenic properties such as angiogenesis and anti-apoptosis. Therefore, the inhibition of DcR3 with specific inhibitors of DcR3 might provide new treatment modalities in breast cancer patients. TL1A, a novel cytokine of the TNF family, is known to bind to DcR3 with high affinity and specificity. The binding of TL1A to DcR3 results in the inhibition of DcR3 anti-cancer activity. Therefore, we speculate that the treatment of breast cancer patients with TL1A will inhibit excess DcR3 expression thus resulting in inhibition of tumor growth and metastasis. Therefore, we propose to investigate the therapeutic potential of soluble human recombinant TL1A (rhTL1A) in preventing DcR3-positive breast cancer metastasis by studying two aims in this study. First, we propose to develop safe and efficacious soluble recombinant TL1A (rhTL1A) protein using human mammalian cell protein expression system. Second, to test the efficacy of rhTL1A in inhibiting tumor growth and spread, we will inject DcR3 expressing human breast cancer cells to mice followed by rhTL1A treatment. The results will be decided on differences in sizes of primary tumors and the severity of metastasis between mice treated with or without rhTL1A. Undoubtedly, the positive outcome of our study will provide not only new insight into the mechanism underlying the development of breast cancer metastasis but also the rationale for developing a therapeutic rhTL1A for future clinical use.
Public Health Relevance: Once breast cancer metastasizes to other parts of the body, there is no cure and in this year alone, it is estimated that 40,170 women in this country will die from breast cancer. Therefore, discovering effective therapeutic agents to combat metastatic breast cancer remains a critical medical challenge. We have discovered the high expression of soluble DcR3 in metastatic breast cancer. DcR3 has been known for its multiple pro-cancer properties. A novel cytokine, TL1A, was shown to inhibit DcR3 pro-cancer activity. Therefore, we hypothesize that TL1A can be developed as anti-cancer agent to target excess DcR3 in breast cancer patients. To test this hypothesis, we propose to evaluate the potential therapeutic effects of recombinant TL1A in an animal model of DcR3-positive breast cancer metastasis. We expect that the positive outcome of this study will provide a rationale for further developing a safe and efficacious TL1A protein drug that can provide survival benefits to breast cancer patients.
Thesaurus Terms: "affinity; Animal Model; Animal Models And Related Studies; Anti-Angiogenesis; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; Antiangiogenesis; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Apoptosis; Apoptosis Pathway; Armpit; Axilla; Axillary; Binding; Binding (Molecular Function); Blood Plasma; Blood Serum; Body Part; Breast Cancer Cell; Breast Cancer Treatment; Cachectin Receptors; Cancer Cause; Cancer Drug; Cancer Etiology; Cancer Patient; Cancer Screening For Patients; Cancer Treatment; Cancer Cell Line; Cancer Of Breast; Cancers; Carcinoma; Cell Culture System; Cell Death, Programmed; Cell/Tissue, Immunohistochemistry; Cells; Cessation Of Life; Chemotherapeutic Agents, Neoplastic Disease; Clinical; Computer Programs; Computer Software; Country; Dif; Death; Development; Disseminated Malignant Neoplasm; Distal; Drug Kinetics; Drugs; Elisa; Enzyme-Linked Immunosorbent Assay; Epithelial Neoplasms, Malignant; Epithelial Tumors, Malignant; Evaluation; Exclusion; Family; Feasibility Studies; Future; Half-Life; Half-Lifes; High Prevalence; Human; Human Breast Cancer Cell; Human Cell Line; Human, General; Ihc; Immunohistochemistry; Immunohistochemistry Staining Method; Inguinal Lymph Node; Inguinal Lymph Node Group; Investigators; Ions; Lung; Lymph Node Proper; Mmg; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Malignant Tumor Of The Breast; Malignant Neoplasm Of Breast; Mammalian Cell; Mammals, Mice; Mammogram; Mammography; Man (Taxonomy); Man, Modern; Measures; Medical; Medication; Metastasis; Metastasize; Metastatic Cancer; Metastatic Malignant Neoplasm; Metastatic Neoplasm; Metastatic Tumor; Mice; Modality; Molecular Interaction; Murine; Mus; Nature; Neoplasm Metastasis; Oncogenesis; Outcome; Outcome Study; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Plasma; Primary Neoplasm; Primary Tumor; Production; Property; Property, Loinc Axis 2; Proteins; Receptor Protein; Recombinants; Reporting; Research Personnel; Researchers; Respiratory System, Lung; Reticuloendothelial System, Lymph Node; Reticuloendothelial System, Serum, Plasma; Scid; Scid Mice; Screening For Cancer; Secondary Neoplasm; Secondary Tumor; Series; Serum; Serum, Plasma; Severe Combined Immunodeficient Mice; Severities; Site; Software; Solid Neoplasm; Solid Tumor; Specificity; Survival Rate; System; System, Loinc Axis 4; Tl1a Protein, Human; Tnf; Tnf A; Tnf Ligand-Related Molecule 1; Tnf Receptor Family Protein; Tnf Receptor Superfamily; Tnf Receptors; Tnf Gene; Tnfr; Tnfsf15; Tnfsf15 Protein, Human; Tnfsf2; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Travel; Tumor Angiogenesis; Tumor Cell Migration; Tumor Necrosis Factor Gene; Tumor Necrosis Factor Ligand Superfamily Member 15; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor Receptor Family; Tumor Necrosis Factor Receptor Superfamily; Tumor Tissue; Tumor-Specific Treatment Agents; Underarm; United States; Vegi Protein, Human; Vascular Endothelial Growth Inhibitor; Woman; Xenograft Model; Analytical Method; Angiogenesis; Antiangiogenesis Therapy; Anticancer Agent; Anticancer Drug; Anticancer Therapy; Cancer Metastasis; Cancer Therapy; Combat; Computer Program/Software; Cytokine; Density; Drug/Agent; Early Cancer Detection; Efficacy Testing; Epithelial Carcinoma; Flasks; Gene Product; Human Tnfsf15 Protein; In Vivo; Infiltrating Duct Carcinoma; Inhibitor; Inhibitor/Antagonist; Insight; Lymph Gland; Lymph Nodes; Malignancy; Malignant Breast Neoplasm; Model Organism; Neoplasm/Cancer; Novel; Prevent; Preventing; Protein Expression; Public Health Relevance; Pulmonary; Receptor; Severe Combined Immune Deficiency; Tumor; Tumor Growth; Tumor Necrosis Factor (Ligand) Superfamily, Member 15, Human; Tumorigenesis; Tumorigenic; Vascular Endothelial Growth Inhibitor, Human"
