Targeting Deceoy Receptor 3 in Breast Cancer

DESCRIPTION (provided by applicant): Breast cancer is the leading cause of cancer deaths in the United States. In this year alone, approximately 40,480 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 an important medical challenge. We have recently discovered increased expression of decoy recepto r 3 (DcR3), a soluble receptor in the tumor necrosis factor receptor family, in invasive breast cancer. In particular, the rate of DcR3 expression was significantly higher in invasive ductal carcinoma with lymph node metastasis compared to carcinoma withou t lymph node metastasis. DcR3 possesses properties that can enhance tumor growth and spread. DcR3 can prevent programmed cell death (apoptosis) and it can promote angiogenesis and it acts as an immune suppressor. Hence, we speculate that increased DcR3 exp ression in breast cancer might provide a favorable condition for breast tumor growth and in particular metastasis. Therefore, we propose to investigate the protective role of neutralizing monoclonal antibody (mAb) in preventing DcR3-mediated breast cancer metastasis by studying two aims in this phase-I feasibility study. First, we propose to establish human breast cancer cells expressing sufficient level of soluble DcR3. Second, to test the efficacy of the mAb in inhibiting tumor growth and spread, we will inject soluble DcR3 expressing breast cancer cells to mice followed by mAb treatment. The results will be decided on differences in sizes of primary tumors and the severity of metastasis between mice treated either with neutralizing or control mAb. Undoubt edly, 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 highly efficacious humanized therapeutic anti-DcR3 neutralizing mAb fo r future clinical use. PUBLIC HEALTH RELEVANCE: Breast cancer is the leading cause of cancer related death in the United States. Early cancer detection via mammography has contributed to increased survival rate of breast cancer patients. However, once brea st cancer spreads to other parts of the body (metastasis), there is no cure and in this year alone, it is estimated that 40,480 women in this country will die from breast cancer. Therefore, discovering effective therapy for metastatic breast cancer remains a critical medical challenge. We have discovered increased expression of a novel protein in metastatic breast cancer. This protein has many properties that can enhance tumor growth and in particular metastasis. Therefore, we speculate that increased expre ssion of this soluble protein in breast cancer might provide a favorable condition for breast cancer growth and spread and that the inhibition of the protein will prevent the development of breast cancer. To test this hypothesis, we propose to evaluate the protective role of the inhibitor of this soluble protein in breast cancer risk using an animal model. We expect that the positive outcome of this study will provide new understanding of breast tumor biology and a rationale for further developing efficacio us therapeutic drug to target this novel protein that can provide survival benefits to breast cancer patients.