p53 and cancer stem cells

The role of p53 in the biology of mammary epithelial stem cells (SC) is well established. p53 may counteract SC expansion by several mechanisms, including restriction of self-renewing divisions and block of reprogramming of somatic/ progenitor cells into SCs. p53 regulates the polarity of cell division in mammary SCs. p53 is often inactivated by loss or mutation in breast cancer. This inactivation favors symmetric divisions of cancer SCs, contributing to tumor growth. Two recent studies demonstrate an unexpected link between p53 and stem cell biology that include a metabolic pathway, the mevalonate pathway. Freed-Pastor and colleagues studied the effects of mutated p53 on breast cancer cells. They showed that depletion of the mutated form of p53 reverses the oncogenic potential of breast cancer cell lines by inducing a normal-like phenotype characterized by the formation of acinilike structures. Ginestier et al. studied the pathways important to the biology of breast cancer stem cells (BCSCs). They compared the gene expression profiles of breast cancer cell lines in suspension (tumorospheres, supposed to be enriched in BCSCs) and adherent cultures. Genes of the mevalonate pathway were overexpressed in the tumorospheres. The mevalonate pathway leads to cholesterol synthesis, protein farnesylation and protein geranylgeranylation. By modulating the pathway with inhibitors specific to each of these three end products, both studies identified protein geranylgeranylation as the important mediator of both p53-mutated oncogenic effects p53 and cancer stem cells The mevalonate connexion