TGF-Beta signaling represents a major tumor suppressor pathway. Loss of the TGF-Beta response is a hallmark in human cancer. However, the mechanisms underlying TGF-Beta resistance in breast cancer have not been elucidated. Anaplastic Lymphoma Kinase ALK is a tyrosine receptor kinase of insulin superfamily. IBC is relatively rare but the most lethal subtype of breastcancer. Thus, it is important to identify biomarkers, understand better current therapies and find new potential therapies for IBC. Our long-term goal is to understand the mechanisms underlying TGF-Beta resistance in human cancer. The short-term strategy o four research is to focus on ALK-induced inactivation of Smad4 in breast cancer. Our unifying hypothesis is that ALK causes TGF-Beta resistance through Smad4 inactivation and disrupts the growth constraints exerted by TGF-Beta signaling to promote breast tumorigenesis. To test our hypothesis, we propose the following specific aims to achieve our goals 1. Investigate in vivo and clinical relevance of Smad4 tyrosine phosphorylation in breast cancer 2. Determine the role of ALK-mediated Smad4 phosphorylation in TGF-Beta resistance in breast cancer 3. Elucidate the molecular mechanisms underlying Smad4 tyrosine phosphorylation. This proposal will contribute significantly to breast cancer prevention and treatment.