Loss of p53 function is invariably associated with cancer. Its role in tumor growth was recently linked to its effects on cancer stem cells (CSCs), although the underlying molecular mechanisms remain unknown. Here, we show that c-myc is a transcriptional target of p53 in mammary stem cells (MaSCs) and is activated in breast tumors as a consequence of p53 loss. Constitutive Myc expression in normal mammary cells leads to increased frequency of MaSC symmetric divisions, extended MaSC replicative-potential, and MaSC-reprogramming of progenitors, whereas Myc activation in breast cancer is necessary and sufficient to maintain the expanding pool of CSCs. Concomitant p53 loss and Myc activation trigger the expression of 189 mitotic genes, which identify patients at high risk of mortality and relapse, independently of other risk factors. Altogether, deregulation of the p53:Myc axis in mammary tumors increases CSC content and plasticity and is a critical determinant of tumor growth and clinical aggressiveness.
Myc is overexpressed and deregulated in breast tumors because of p53 signaling attenuation
Myc activation favors SC symmetric divisions and SC reprogramming of progenitors
Myc activation is necessary and sufficient to sustain the cancer SC phenotype
Expression of 189 mitotic p53:Myc targets identifies high-risk breast cancer patients
Santoro et al. demonstrate the existence of a regulatory axis instructed by the tumor-suppressor p53, executed by the Myc oncogene, and involving 189 p53:Myc targets. The authors show that activation of this axis maintains the expanding pool of cancer stem cells (SCs), thus promoting tumor growth, and predicts adverse prognosis.