Editors' ChoiceCancer

p53 Promotes Polarity

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Science Signaling  29 Sep 2009:
Vol. 2, Issue 90, pp. ec319
DOI: 10.1126/scisignal.290ec319

Stem cells can divide symmetrically (to yield two daughter stem cells) or asymmetrically (to yield a daughter stem cell and another cell that will eventually differentiate). A relationship between a loss of cell polarity during stem cell division and tumorigenesis has been demonstrated in Drosophila but not in mammals. Cicalese et al. (see also Aparicio and Eaves) cultured primary cells from mammary tissues of wild-type mice, mice expressing the ErbB2 oncogene in mammary epithelium, and mice lacking p53 so that the cells formed floating colonies called mammospheres. The ErbB2 and p53–/– mammospheres contained higher numbers of stem cells that were more rapidly dividing and possessed greater potential for self-renewal. Intriguingly, staining with the membrane dye PKH-26 and immunofluorescence for Numb showed that the majority of wild-type mammary stem cells divided in an asymmetric fashion, whereas most of the ErbB2 and p53–/– mammary stem cells divided symmetrically. Activation of p53 in response to DNA damage was blunted in ErbB2 mammospheres compared with wild-type mammospheres. Treatment with Nutlin, an inhibitor of the ubiquitin E3 ligase (Mdm2) that targets p53 for proteasomal degradation, reduced the number of ErbB2 mammospheres but had no effect on that of wild-type mammospheres. Furthermore, Nutlin-treated ErbB2 mammospheres formed smaller tumors when implanted into mice when compared with untreated ErbB2 mammospheres, and Nutlin treatment of ErbB2 mice (which spontaneously develop tumors) reduced the number of stem cells in tumors and tumor volume. Thus, restoring p53 function in cancer stem cells may promote asymmetric divisions and decreased capacity for self-renewal.

A. Cicalese, G. Bonizzi, C. E. Pasi, M. Faretta, S. Ronzoni, B. Giulini, C. Brisken, S. Minucci, P. P. Di Fiore, P. G. Pelicci, The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083–1095 (2009). [PubMed]

S. Aparicio, C. J. Eaves, p53: A new kingpin in the stem cell arena. Cell 138, 1060–1062 (2009). [PubMed]

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