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.

Molecular classification of prostate cancer using curated expression signatures

“…They showed that there is an overlap between the ESC and iPSC signatures and p53 mutant tumors, whereas expression of the PRC2 signature is enhanced in breast tumors with a wild-type p53 gene. Thus, these expression signatures defined subsets of breast or lung cancers that reflected both the mutation profiles and clinical outcomes (4). A similar result was independently obtained in liver cancers with p53 mutations and a poor outcome (5).…”

“…They demonstrated that this ESC signature predominantly corresponded to the subclass of breast tumors termed the basal or triple-negative tumors and to the Her-2 positive tumors. Mizuno et al (4) confirmed this observation and further demonstrated that tumors with the ESC signature almost always had p53 mutations or an inactive p53 function. These are typically tumors with poor clinical outcome, commonly associated with relapse and high mortality.…”

“…These are typically tumors with poor clinical outcome, commonly associated with relapse and high mortality. In addition, Mizuno et al (4) defined expression signatures for induced pluripotent stem cells (iPSCs) and the polycomb repressive complex-2 (PRC2). They showed that there is an overlap between the ESC and iPSC signatures and p53 mutant tumors, whereas expression of the PRC2 signature is enhanced in breast tumors with a wild-type p53 gene.…”

TEAD activity is restrained by MYC and stratifies human breast cancer subtypes

“…The enrichment of specific gene signatures per patient was performed using a GSEA-like algorithm as described previously using a Kolgomorov-Smirnov test for normality. 5,24 The C3 motif gene set was downloaded from the Molecular Signatures Database (MSigDB, http://software.broadinstitute. org/gsea/msigdb) and used for subsequent analyses of breast cancer patients and gene set enrichment analysis (GSEA).…”

Reprogramming and Carcinogenesis—Parallels and Distinctions

“…loss was associated with poorly differentiated thyroid cancers (Fagin et al, 1993), breast cancer (de Cremoux et al, 1999;Kochhar et al, 2005;Miller et al, 2005;Mizuno et al, 2010) lung cancer (Junttila et al, 2010), hematopoetic system malignacies (Chylicki et al, 2000;Feinstein et al, 1992), collateral mutations of p53 and PTEN are the most common tumor suppressor aberrations in glioblastomas, which are poorly differentiated, developmentally plastic brain tumors derived from the neuronal stem/progenitor cells (Zheng et al, 2008). Deletion of the three RB family proteins triggers the reprogramming of MEFs to generate CSC-like cells ).…”