Preventing Transformation

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Science  28 Sep 2007:
Vol. 317, Issue 5846, pp. 1835
DOI: 10.1126/science.317.5846.1835b

The oncogene c-Myc, which encodes a transcription factor, is well known for its ability to transform cells. However, not all cells are equally sensitive to c-Myc-induced transformation. Partanen et al. compared the responses of organized epithelial acini and of disorganized or immature acini formed from mammary epithelial cells to the transforming ability of a form of c-Myc (MycERtm) activated by cell exposure to tamoxifen. When epithelial cells were plated in Matrigel (a three-dimensional cell culture environment prepared from an extract of extracellular matrix) and MycERtm was activated right away, the cells formed misshapen acini and some cells could be seen in the luminal space. On the other hand, cells grown in the absence of activated c-Myc formed symmetrical acini with an empty lumen, and the acini were smaller. If tamoxifen was added after the cells had already formed organized acinar structures, then c-Myc lost its oncogenic activity: The morphology and size of the acini were unchanged, and cell proliferation was not induced. Cells in which the kinase LKB1 (implicated in the establishment of cellular polarity) was silenced formed disorganized acini with disrupted cell polarity when cultured in Matrigel. However, these LKB1-deficient cells did become quiescent. Activation of c-Myc in the LKB1-deficient cells stimulated reentry into the cell cycle, thus confirming the potency of epithelial organization as a brake for oncogenic transformation. The authors also addressed the apoptotic activity of c-Myc, which sensitized cells of fully organized acini to TRAIL (a death-inducing agent that activates apoptosis) and revealed that both TRAIL and Myc were required to promote apoptosis. However, in LKB1-deficient cells with disorganized acini or immature acini, the activation of MycERtm or TRAIL caused apoptosis, and these two agents had an additive effect on cell death. Thus, disorganized epithelia are more sensitive to both the cell-proliferative and apoptotic effects of c-Myc. — NRG

Proc. Natl. Acad. Sci. U.S.A. 104, 14694 (2007).

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