title: Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures.
abstract: Breast cancer comprises a heterogeneous set of diseases distinguishable from one another by pathologic presentation and molecular signatures. However, each breast cancer subtype is also heterogeneous. Some of the heterogeneity may be attributable to genetic instability, but recent data emphasize that developmental plasticity may also contribute. The p53 tumor suppressor could constitute a nodal control point underlying both sources of heterogeneity because it is frequently inactivated during malignant progression and has recently been shown to function as a potent barrier preventing fully differentiated cells from reverting to pluripotent stem cells after expression of appropriate oncogenes. Using archival microarray datasets, we tested the hypothesis that a p53 mutation could allow cells within a tumor to acquire a stem cell-like state by looking for coordinate expression of stem cell identity genes. We show that breast and lung cancers with p53 mutations do exhibit stem cell-like transcriptional patterns. Such tumors were also depleted for differentiation genes regulated by the polycomb repressor complex 2. These data are consistent with a model in which loss of p53 function enables acquisition of stem cell properties, which are positively selected during tumor progression.
authors.affiliation: The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540, USA.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mizuno
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Spike
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Wahl
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53