Boxer, R. B., Jang, J. W., Sintasath, L. & Chodosh, L. A. Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. Cancer Cell 6, 577-586

Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Cancer Cell (Impact Factor: 23.52). 01/2005; 6(6):577-86. DOI: 10.1016/j.ccr.2004.10.013
Source: PubMed


Recent studies of oncogene dependence in conditional transgenic mice have suggested the exciting possibility that transient or prolonged MYC inactivation may be sufficient for sustained reversal of the tumorigenic process. In contrast, we report here that following oncogene downregulation, the majority of c-MYC-induced mammary adenocarcinomas grow in the absence of MYC overexpression. In addition, residual neoplastic cells persist from virtually all tumors that do regress to a nonpalpable state and these residual cells rapidly recover their malignant properties following MYC reactivation or spontaneously recur in a MYC-independent manner. Thus, MYC-induced mammary tumor cells subjected to either brief or prolonged MYC inactivation remain exquisitely sensitive to its oncogenic effects and characteristically progress to a state in which growth is MYC-independent.

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Available from: Louis Sintasath, May 27, 2015
    • "These previous works have shown that oncogene expression is not only required for initiation of cancer but also for the maintenance of the disease and have kept oncogenes firmly in focus as therapeutic targets. In mouse models where oncogene expression is driven by tissue-specific promoters, tumours arise at high frequencies , but disappear again when the inducing stimulus is switched off ( Chin et al., 1999 ; Huettner et al., 2000 ; Boxer et al., 2004 ), suggesting that oncogenes are the Achilles ' heel of cancers ( Weinstein, 2002 ). Overall, these observations define a homogenous role for oncogenes within cancer cells ( Figure 1 A), as brief inactivation of the single tumour-inducing oncogene can cause remission in these model systems. "
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    • "Experimental mouse models have been a particularly tractable approach to interrogating the mechanism of oncogene addiction. Transgenic mouse models employing strategies that enable the conditional expression of oncogenes have been used to illustrate that cancers initiated by an oncogene, such as MYC, RAS, BCR-ABL, MET, and BRAF, are reversible upon suppression of the oncogene [1,35-40]. "
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    • "Using a regulated reversible system, the sustained requirement for oncogenic activity in a fully established tumor can be directly demonstrated by extinguishing the expression of the transgene and monitoring the phenotypic consequences in the tumor. For example, this approach showed that persistent RAS activation is required for melanoma maintenance (Wong and Chin, 2000), persistent MYC-activation is required for maintenance of hematopoietic tumors and a subset of breast adenocarcinoma (Boxer et al., 2004), mutant isocitrate dehydrogenase-2 (IDH2) has a proto-oncogenic role in leukemia initiation and maintenance (Kats et al., 2014), and oncogenic BRAF is required for tumor growth and maintenance in melanoma models (Hoeflich et al., 2006). Also, the overexpression of Mad2 in transgenic mice induces a variety of neoplasias and the acceleration of myc-induced lymphomagenesis; however, continued overexpression of Mad2 is not required for tumor maintenance (Sotillo et al., 2007; Sotillo et al., 2010). "
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