Abstract
Oncogene addiction is a cellular property by which cancer cells become highly dependent on the expression of oncogenes for their survival. Oncogene addiction can be exploited to design molecularly targeted drugs that kill only cancer cells by inhibiting the specific oncogenes. Genes and cell lines exhibiting oncogene addiction, as well as the mechanisms by which cell death is induced when addicted oncogenes are suppressed, have been extensively studied. However, it is still not fully understood how oncogene addiction is acquired in cancer cells. Here, we take a synthetic biology approach to investigate whether oncogenic mutation or oncogene expression suffices to confer the property of oncogene addiction to cancer cells. We employed human mammary epithelium-derived MCF-10A cells expressing the oncogenic KRAS or BRAF. MCF-10A cells harboring an oncogenic mutation in a single-allele of KRAS or BRAF showed weak transformation activity, but no characteristics of oncogene addiction. MCF-10A cells overexpressing oncogenic KRAS demonstrated the transformation activity, but MCF-10A cells overexpressing oncogenic BRAF did not. Neither cell line exhibited any oncogene addiction properties. These results indicate that the introduction of oncogenic mutation or the overexpression of oncogenes is not sufficient for cells to acquire oncogene addiction, and that oncogene addiction is not associated with transformation activity.
Highlights
Most human cancers develop over a long period of time, from a few years to several decades, as mutations accumulate in various proto-oncogenes and tumor suppressor genes [1, 2]
Knock-down of the BRAF gene attenuated the number of colonies in these cell lines, but the effect was stronger in BRAF V600E/+ cells than in KRAS G12V/+ cells (Fig 4F and 4G). These results indicate that oncogenic mutation in KRAS or BRAF is involved in the acquisition of the ability for growth factor-independent and anchorage-independent growth, they are not suitable for evaluation of oncogene addiction because parental cells did not proliferate in the starvation medium and in the soft agar
We examined the association between oncogene addiction and in vitro tumorigenic properties (Fig 7A)
Summary
Most human cancers develop over a long period of time, from a few years to several decades, as mutations accumulate in various proto-oncogenes and tumor suppressor genes [1, 2]. During this process, cancer cells rewire the intracellular signal transduction system by accumulating mutations and epigenetic changes, and acquire the characteristics of malignant tumors (Fig 1). Mutation or overexpression of oncogenes is not sufficient for cells to acquire oncogene addiction. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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