Preventing Transformation

Abstract

The oncogene Myc, which is a transcription factor, is well known for its ability to transform cells. However, not all cells are equally sensitive to Myc-induced transformation. Partanen et al . compared the response of organized epithelial acini and disorganized or immature acini formed from mammary epithelial cells (untransformed MCF10A and immortalized cells) with the transforming ability of a conditionally activated form of Myc (MycER tm ) that is activated by exposing the cells to tamoxifen. When the cells were plated in Matrigel (a three-dimensional matrix) and MycER tm was continuously activated, the cells formed misshapen acini with cells in the luminal space. Cells grown in the absence of activated Myc formed symmetrical acini that had hollow lumens lacking cells, and the acini were smaller because cell proliferation stopped sooner than it did in the cells with activated MycER tm . However, if tamoxifen was added after the cells grown on Matrigel had formed established organized acinar structures, then 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, which is implicated in establishment of cellular polarity, was silenced formed disorganized acini with disrupted cell polarity when plated in Matrigel. However, these LKB1-deficient cells did become quiescent. Activation of Myc in these quiescent LKB1-deficient cells of the disorganized acini did stimulate reentry into the cell cycle, thus confirming the importance of epithelial organization as a brake for oncogenic transformation. The authors also addressed the apoptotic activity of Myc. Myc sensitized cells of fully organized acini to TRAIL (a death-inducing agent that activates apoptosis), which means that both TRAIL and Myc were required to promote apoptosis. However, in LKB1-deficient disorganized acini or immature acini, activation of MycER tm 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 Myc. J. I. Partanen, A. I. Nieminen, T. P. Mäkelä, J. Klefstrom, Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization. Proc. Natl. Acad. Sci. U.S.A. 104 , 14694-14699 (2007). [Abstract] [Full Text]