Journal
ONCOGENE
Volume 33, Issue 30, Pages 3992-4002Publisher
SPRINGERNATURE
DOI: 10.1038/onc.2013.368
Keywords
Her2; ERBB2; Myc; cancer stem cell; transcriptomics; oncogene cooperation
Funding
- International Postgraduate Research Scholarship (IPRS)
- Beth Yarrow Memorial Award in Medical Science
- Victoria Taylor, Sydney Breast Cancer Foundation
- CCNSW
- Colin Biggers & Paisley, Sydney
- Early Career Fellowship from the National Breast Cancer Foundation Australia
- Cancer Institute NSW Clinical Research Fellowship [10-CRF 1-07]
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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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