There have been significant gains in our understanding of the molecular diversity of human breast cancer, and this knowledge has led us away from the "one-size-fits-all" therapeutic approaches that have been used in the treatment of this spectrum of diseases that had previously been treated as a single, uniform clinical problem. Consequently, we have now developed insights into the management of hormone receptor-positive disease (i.e., ER+/PR+ breast cancers comprising ~60% of breast malignancies), peptide growth factor receptor altered disease (i.e., HER2+ breast cancers comprising ~20%-25% of cases), and the remaining subgroup characterized by the fact that they lack these alterations (i.e., triple-negative breast cancers comprising ~15%-18% of cases). Clinical outcome data indicate that these diverse molecular subtypes have equally diverse responses to the traditional therapeutic approaches. We now treat the specific breast cancer subtypes based on this knowledge. This has resulted in significant gains in efficacy with improvements in both progression-free and overall survival rates as well as improvements in safety with decreases in unnecessary toxicities associated with therapies that are unlikely to be helpful. Despite these gains, there are still some 39,000 women each year who succumb to breast cancer, and given these numbers, there is definite need for significant improvements in our treatment paradigms. It is the objective of this Innovator Award to develop new insights that will result in the development of novel treatment initiatives for all of the current therapeutic subtypes. In addition, we will investigate mechanisms of de novo and acquired resistance to established regimens as well as the newer targeted therapeutics used for specific subtypes. Our approach will be to utilize a series of well-characterized human breast cancer in vitro and in vivo models that were very instrumental in initially differentiating the HER2+ subtype from the others. These efforts will be combined with genomic information derived from existing, well-annotated human breast cancer tissue banks using state-of-the-art bioinformatics platforms to assist in integrating the relevant cell line, xenograft, and human tissue information regarding potential "disease-driving" genetic and/or signaling pathway alterations for the specific subtypes. The intent will be to use the new experimental data arising from the research supported by this Innovator Award to develop novel and innovative therapeutic translational study protocols for clinical testing in the various breast cancer subtypes. To accomplish this, these preclinical and laboratory research initiatives will be linked to an effective and dynamic clinical trials network that has been developed to test novel therapeutic strategies while obtaining clinical material to better understand the optimal approaches to applying these new strategies to better treat women challenged with breast cancer. It is envisioned that all of these clinical studies will be supported by various industry sponsors, depending on the therapeutic agents and genes/pathways being studied.