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

R Nair, DL Roden, WS Teo, A McFarland, S Junankar… - Oncogene, 2014 - nature.com
R Nair, DL Roden, WS Teo, A McFarland, S Junankar, S Ye, A Nguyen, J Yang, I Nikolic…
Oncogene, 2014nature.com
Abstract 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 …
Abstract
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.
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