While treatment options for women diagnosed with breast cancer are becoming more refined, 1 in 4 patients still die of the disease. My work has recently demonstrated that the molecule CD73 is involved in the progression of breast cancer and that blocking CD73 inhibits tumor growth. CD73 is present in 2 subtypes of breast cancer: triple-negative breast cancer and HER2+ breast cancer. Triple-negative breast cancer accounts for 15% of all breast cancers and is characterized by a worse prognosis. HER2+ breast cancer accounts for 30% of breast cancers and while trastuzumab has improved treatment of HER2+ breast cancer, more than 15% of patients eventually develop metastatic disease. Given these characteristics, there remains an unmet medical need for new therapies for both triple-negative breast cancer and HER2+ breast cancer. We here propose to assess the therapeutic activity of combining anti-CD73 therapy with trastuzumab therapy and combining anti-CD73 with new immune-modulators currently in clinical development. Based on our studies, the development of anti-CD73 treatments may significantly enhance the standard of care for breast cancer. It is our contention that this proposal has great potential in the creation of new avenues of research and new treatment options for patients diagnosed with type triple-negative or HER2+ breast cancer.