Breast cancer is the second most common cause of cancer related death in women. One subtype of breast cancer is characterized by the overexpression of a receptor molecule, called HER2. When HER2 is overexpressed, breast cells are stimulated to divide inappropriately. The importance of HER2 overexpression in breast cancer pathogenesis has been dramatically illustrated by the ability of antibodies against HER2 to improve survival of HER2+ breast cancer patients. However, these antibodies are not a panacea, and many women with HER2+ disease will still die of their disease. We have found that a molecule that normally regulates HER2, called protein-tyrosine phosphatase 1B (PTP1B), is required for HER2-overexpressing cells to cause breast cancer, at least in mice. Specifically, mice rendered genetically deficient for PTP1B are resistant to the ability of HER2 over-expression to induce tumors. However, PTP1B also affects several other pathways in mice - for example, it regulates insulin responses and body weight - so the exact reason why PTP1B deficiency causes breast cancer resistance remains unclear. We will determine how PTP1B deficiency causes breast cancer resistance at the cellular and molecular level, and also determine whether PTP1B deficiency and/or inhibition of PTP1B activity, prevents or reverses carcinogenesis in human HER2+ breast cancer cell lines.