HER2 receptor tyrosine kinase is overexpressed in a high percentage of human breast tumors. HER2 signaling activates key downstream pathways involved in cell proliferation and cell survival including RAS-RAF-MEK-ERK and PI3K-AKT. Deregulation of c-MYC activity, associated with increased c-MYC protein stability, is also observed in human breast cancers. Since c-MYC protein stability and activity are regulated by interdependent phosphorylation events controlled by RAS-ERK and PI3K-AKT pathways, we investigated the role of HER2 in post-translational regulation of c-MYC protein stability and oncogenic activity. We found that HER2 signaling increases c-MYC protein stability and this associates with increased phosphorylation at Serine 62 (Ser62), an activating modification on c-MYC. Moreover, inhibition of HER2 decreases Ser62 phosphorylation as well as c-MYC protein stability and activity. We have generated a novel mouse model in which we can conditionally express deregulated, but physiological expression levels of c-MYC in combination with activated HER2. In this model, expression of activated HER2 dramatically cooperates with low deregulated expression of Myc for tumorigenesis. Resulting tumors have either a basal or luminal phenotype with HER2 amplification. Interestingly, recent descriptions of these two HER2 subtypes in human breast cancer indicate differential therapeutic sensitivity. Thus, our new mouse model provides a robust HER2+ breast tumor mouse model relevant for pre-clinical testing. We have investigated the efficacy of either in vivo pharmacological inhibition of HER2 activity using Lapatinib, or inactivation of c-MYC through upregulation of Protein Phosphatase 2A (PP2A) activity in this model. Both of these therapeutic strategies can decreases phosphorylation of c-MYC at Ser62 and suppresses tumor progression. Furthermore, combination therapy, inactivating HER2 kinase activity and activating PP2A activity, leads to tumor shrinkage. This work expands our understanding of HER2’s oncogenic mechanisms, modes of c-MYC activation in breast cancer, and new therapeutic strategies for the treatment of HER2+ breast cancer.