Editors' ChoiceCancer

The Other Path to Cancer

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Science Signaling  17 Nov 2009:
Vol. 2, Issue 97, pp. ec374
DOI: 10.1126/scisignal.297ec374

The stable switch of normal cells to a transformed phenotype characterized by uncontrolled and invasive growth is central to the development of cancer. Iliopoulos et al. describe a mechanism for an epigenetic switch (that is, a stable phenotypic change, retained through multiple generations in proliferating cells, that is not mediated by alteration of DNA sequence) that promotes transformation in a cancer model based on human breast cancer cells. The cells can be induced to undergo transformation by overexpression of the Src oncogene, which encodes a protein tyrosine kinase. In fact, activation of a fusion protein of Src combined with the ligand-binding domain of the estrogen receptor (which can be precisely activated by treatment of cells with the estrogen receptor agonist tamoxifen) for just 5 minutes produced cells that adopted a transformed phenotype that was stable over at least 12 generations. The authors teased apart a mechanism that could explain this switchlike behavior through activation of an inflammatory signaling pathway that includes a positive feedback mechanism that allows it to remain active after removal of the original stimulus. This is particularly intriguing because inflammation is strongly associated with cancer formation in humans and other organisms. Activation of Src led to increased activity of the transcription factor NF-κB, a critical mediator of inflammatory responses. A key target of NF-κB in this system was lin-28B, an RNA-binding protein that transcriptionally and posttranscriptionally inhibits accumulation of the microRNA let-7. let-7 interacts with, and inhibits transcription of, mRNA encoding interleukin 6 (IL-6), a key inflammatory cytokine thought to contribute to various human cancers. IL-6 signals through its receptor to activate NF-κB, thus creating the positive feedback loop. Disruption of any step in the loop resulted in loss of transformation, and the loop could be started by stimulation of any one of the defined steps. Although acknowledging the possible limitations of the model, which uses an immortalized cell line and an engineered oncogene, the authors argue that the signaling events defined in the model are known to be associated with certain human cancers. Thus, the switch mechanism they describe could allow a transient event like inflammation or exposure to an environmental factor to produce a long-lasting cancerous effect analogous to mutation of a tumor suppressor gene or activation of an oncogene.

D. Iliopoulos, H. A. Hirsch, K. Struhl, An epigenetic switch involving NF-κB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009). [PubMed]

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