Introduction; 20 % of breast cancers amplify and overexpress the HER2 oncogene. Regardless of the proven efficacy of HER2 inhibitor Trastuzumab, most of the patients respond poorly or become resistant to the treatment. Since the HER2 amplicon at 17q12-21 contains multiple genes, we wanted to explore the role of the HER2 co-amplified genes in breast cancer. Methods; We integrated data on the HER2 amplicon size from 71 HER2+ tumors and 10 cell lines with functional RNAi analysis of 23 core amplicon genes with several phenotypic endpoints in Trastuzumab responding and non-responding HER2+ breast cancer cells. Results; Silencing of HER2 caused a greater growth arrest in the responding compared to the non-responding cell lines, indicating that the resistant cells are inherently less dependent on the HER2 pathway. Several co-amplified genes also had growth inhibitory effects when silenced, indicating that they are needed to sustain the growth of breast cancer cells. Importantly, co-silencing of the PPP1R1B, STARD3 and PERLD1 together with HER2 led to a synergistic inhibition of cell viability as well as AKT and S6K phosphorylation. Conclusions; These results indicate that breast cancer cells become addicted to the amplification of several genes in the HER2 amplicon and that simultaneous targeting of these genes may be therapeutically beneficial. The observed synergistic effects seem to culminate to the PI3K-AKT complex, supporting the ongoing efforts to develop inhibitors for these pathways for combinatorial treatment of HER2+ breast cancers.