The oncogenic isoform of HER2, HER2Δ16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2Δ16 drives metastasis and resistance to multiple therapeutic interventions including tamoxifen and trastuzumab. The research carried out in this dissertation investigated the molecular mechanisms underlying HER2Δ16 activity contributing to primary trastuzumab resistance. In recent years microRNAs have been shown to influence multiple aspects of tumorigenesis and tumor cell response to therapy. Accordingly, the HER2Δ16 oncogene alters microRNA expression to promote endocrine resistance. With the goal of identifying microRNA suppressors of HER2Δ16 oncogenic activity, we investigated the contribution of altered microRNA expression to HER2Δ16-mediated tumorigenesis and trastuzumab resistance. Using a gene array strategy to compare the microRNA expression profiles of MCF-7 to MCF-7/HER2Δ16 cells, we found that HER2Δ16 suppresses expression of the miR-7 tumor suppressor. Reestablishing miR-7 expression significantly inhibits HER2Δ16-mediated tumor cell proliferation and migration, as well as sensitizes HER2Δ16-expressing cells to trastuzumab treatment. We propose that miR-7 regulated pathways, including EGFR and Src kinase, represent targets for the therapeutic intervention of refractory and metastatic HER2Δ16-driven breast cancer. Research in the past decade in HER2-positive breast cancer has focused on elucidating the molecular basis of primary and acquired trastuzumab resistance. Our laboratory has shown that critical and clinically important resistance pathways may be deregulated and only revealed during drug treatment. To identify potential resistance pathways deregulated during trastuzumab treatment, we used a phosphoproteomic approach to profile a subset of phosphorylation events after HER2Δ16-overexpressing cells were treated with trastuzumab. We discovered trastuzumab treatment significantly induced activation of ribosomal p70S6 kinase 1 (p70S6K) and aberrant signaling activity of this kinase is implicated in several disease models due to its role in regulating protein synthesis, cell proliferation and survival. Our data indicates that trastuzumab activates p70S6K to promote prosurvival signaling in breast cancer cells with inherent resistance. We propose that p70S6K can be evaluated in HER2-positive breast cancer patients undergoing trastuzumab treatment as a biomarker to predict therapeutic response. Overall, our research establishes that HER2Δ16 expression is an important genetic event in HER2 tumorigenesis and drives trastuzumab refractory breast cancer.