The metastatic spread of tumor cells is a major cause of death in cancer patients. Breast cancer cells metastasize preferentially via the lymphatic system. In fact, the spread of breast cancer via lymphatic vessels to the regional lymph nodes is one of the most important indicators of tumor aggressiveness. At present, however, it remains unknown whether tumor-associated lymphatic vessels play an active role in tumor dissemination. The views regarding the presence of lymphatic vessels in tumors are conflicting, and it remains unclear whether tumors stimulate the formation of new lymphatic vessels, i.e., lymphangiogenesis. The major objective of the proposed study is to assess the significance of lymphangiogenesis for breast cancer metastasis. We will examine the extent of lymphangiogenesis in biopsies from human breast cancers and determine its relationship to tumor metastases. This study is intended to provide a preliminary validation of the prognostic significance of tumor lymphangiogenesis in breast cancer. Furthermore, we will test the hypothesis that expression of lymphangiogenic factors VEGF-C and VEGF-D by tumor cells facilitates metastatic spread in the mouse model of breast cancer metastases. We expect to obtain initial evidence that activation of lymphatic system by tumor cells promotes tumor progression. The understanding of the molecular mechanisms regulating lymphangiogenesis may provide a basis for the early diagnosis of the metastatic potential of breast cancer and for the development of new therapeutic strategies for limiting breast cancer metastasis.