The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells.
Stem-like cells may be integral to the development and maintenance of human cancers. Direct proof is still lacking, mainly because of our poor understanding of the biological differences between normal and cancer stem cells (SCs). Using the ErbB2 transgenic model of breast cancer, we found that self-renewing divisions of cancer SCs are more frequent than their normal counterparts, unlimited and symmetric, thus contributing to increasing numbers of SCs in tumoral tissues. SCs with targeted mutation of the tumor suppressor p53 possess the same self-renewal properties as cancer SCs, and their number increases progressively in the p53 null premalignant mammary gland. Pharmacological reactivation of p53 correlates with restoration of asymmetric divisions in cancer SCs and tumor growth reduction, without significant effects on additional cancer cells. These data demonstrate that p53 regulates polarity of cell division in mammary SCs and suggest that loss of p53 favors symmetric divisions of cancer SCs, contributing to tumor growth.
Cicalese
Angelo
A
Istituto Europeo di Oncologia (IEO), Department of Experimental Oncology at the IFOM-IEO Campus, Milan, Italy.
Bonizzi
Giuseppina
G
Pasi
Cristina E
CE
Faretta
Mario
M
Ronzoni
Simona
S
Giulini
Barbara
B
Brisken
Cathrin
C
Minucci
Saverio
S
Di Fiore
Pier Paolo
PP
Pelicci
Pier Giuseppe
PG
D000818:Animals; D002455:Cell Division; D016764:Cell Polarity; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C508053:ERBB2 protein, human