Insertional mutagenesis in a HER2-positive breast cancer model reveals ERAS as a driver of cancer and therapy resistance

Personalized medicine for cancer patients requires a deep understanding of the underlying genetics that drive cancer and the subsequent identification of predictive biomarkers. To discover new genes and pathways contributing to oncogenesis and therapy resistance in HER2+ breast cancer, we performed...

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Bibliographic Details
Published in:	Oncogene Vol. 37; no. 12; pp. 1594 - 1609
Main Authors:	Ikink, Gerjon J., Boer, Mandy, Bakker, Elvira R. M., Vendel-Zwaagstra, Annabel, Klijn, Chris, ten Hoeve, Jelle, Jonkers, Jos, Wessels, Lodewyk F., Hilkens, John
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-03-2018 Nature Publishing Group
Subjects:	1-Phosphatidylinositol 3-kinase 631/67/1347 631/67/1857 631/67/395 AKT protein Animal models Apoptosis Biological markers Breast cancer Breast carcinoma Cancer genetics Cancer patients Cancer therapies Cancer treatment Carcinogenesis Cell Biology Disease resistance Drug delivery Drug resistance ErbB-2 protein ErbB-3 protein Gene expression Genetic aspects Genetic engineering Genetics Genotypes Guanosine triphosphatases Human Genetics Insertional mutagenesis Internal Medicine MAP kinase Medicine Medicine & Public Health Metabolic pathways Monoclonal antibodies Mutagenesis Mutation Oncology Pharmacogenomics Precision medicine Proteins Ras protein Ribonucleic acid RNA Rodents Signal transduction Targeted cancer therapy Transgenic mice Trastuzumab Tumorigenesis Tumors
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Summary:	Personalized medicine for cancer patients requires a deep understanding of the underlying genetics that drive cancer and the subsequent identification of predictive biomarkers. To discover new genes and pathways contributing to oncogenesis and therapy resistance in HER2+ breast cancer, we performed Mouse Mammary Tumor Virus (MMTV)-induced insertional mutagenesis screens in ErbB2/cNeu- transgenic mouse models. The screens revealed 34 common integration sites (CIS) in mammary tumors of MMTV-infected mice, highlighting loci with multiple independent MMTV integrations in which potential oncogenes are activated, most of which had never been reported as MMTV CIS. The CIS most strongly associated with the ErbB2 -transgenic genotype was the locus containing Eras (ES cell-expressed Ras), a constitutively active RAS-family GTPase. We show that upon expression, Eras acts as a potent oncogenic driver through hyperactivation of the PI3K/AKT pathway, in contrast to other RAS proteins that signal primarily via the MAPK/ERK pathway and require upstream activation or activating mutations to induce signaling. We additionally show that ERAS synergistically enhances HER2-induced tumorigenesis and, in this role, can functionally replace ERBB3/HER3 by acting as a more powerful activator of PI3K/AKT signaling. Although previously reported as pseudogene in humans, we observed ERAS RNA and protein expression in a substantial subset of human primary breast carcinomas. Importantly, we show that ERAS induces primary resistance to the widely used HER2-targeting drugs Trastuzumab (Herceptin) and Lapatinib (Tykerb/Tyverb) in vivo, and is involved in acquired resistance via selective upregulation during treatment in vitro, indicating that ERAS may serve as a novel clinical biomarker for PI3K/AKT pathway hyperactivation and HER2-targeted therapy resistance.
ISSN:	0950-9232 1476-5594
DOI:	10.1038/s41388-017-0031-0