c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer

R Nair, D L Roden, W S Teo, A McFarland, S Junankar, S Ye, A Nguyen, J Yang, I Nikolic, M Hui, A Morey, J Shah, A D Pfefferle, J Usary, C Selinger, L A Baker, N Armstrong, M J Cowley, M J Naylor, C J Ormandy, S R Lakhani, J I Herschkowitz, C M Perou, W Kaplan, S A O'Toole, A Swarbrick

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer.Oncogene advance online publication, 23 September 2013; doi:10.1038/onc.2013.368.