Abstract
A hallmark of human cancer is heterogeneity, reflecting the complex series of changes resulting in the activation of oncogenes coupled with inactivation of tumor suppressor genes. Breast cancer is no exception and indeed, many studies have revealed considerable complexity and heterogeneity in the population of primary breast tumors and substantial changes in a recurrent breast tumor that has acquired metastatic properties and drug resistance. We have made use of a Myc-inducible transgenic mouse model of breast cancer in which elimination of Myc activity following tumor development initially leads to a regression of a subset of tumors generally followed by de novo Myc-independent growth. We have observed that tumors that grow independent of Myc expression have gene profiles that are distinct from the primary tumors with characteristics indicative of an epithelial–mesenchymal transition (EMT) phenotype. Phenotypic analyses of Myc-independent tumors confirm the acquisition of an EMT phenotype suggested to be associated with invasive and migratory properties in human cancer cells. Further genomic analyses reveal mouse mammary tumors growing independent of myc have a higher probability of exhibiting a gene signature similar to that observed for human ‘tumor-initiating’ cells. Collectively, the data reveal genetic alterations that underlie tumor progression and an escape from Myc-dependent growth in a transgenic mouse model that can provide insights to what occurs in human cancers as they acquire drug resistance and metastatic properties.
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Acknowledgements
The MTB/TOM mouse was a kind gift from Lewis A Chodosh. We thank Kenichiro Fujiwara for his assistance in animal husbandry and Rachel E Rempel for her helpful advice. We are grateful to Kaye Culler for her assistance with the manuscript. This work was supported by grants from the NIH (CA104663, CA112952) and grants U01 CA141541 and U01 CA141582 from the National Cancer Institute's Mouse Models of Human Cancers Consortium (RDC). We also thank Ms Katie Bell and Judith Walls of the CCM MMPL for their excellent immunohistochemistry. This work was also supported by grants from the JRN (RO1-CA104663 and U54-CA112952) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
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Dr Nevins’ work has been funded by the NIH. He has received compensation as a member of the scientific advisory boards of the Millennium Pharmaceutical and Qiagen Scientific. In addition, he reports ownership interest in the Expression Analysis Inc. Drs Leung Andrechek and Cardiff declare no potential conflict of interest.
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Leung, J., Andrechek, E., Cardiff, R. et al. Heterogeneity in MYC-induced mammary tumors contributes to escape from oncogene dependence. Oncogene 31, 2545–2554 (2012). https://doi.org/10.1038/onc.2011.433
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DOI: https://doi.org/10.1038/onc.2011.433
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