Prognostic and predictive factors are indispensable tools in the treatment of patients with neoplastic disease. For the most part, such factors rely on a few specific cell surface, histological, or gross pathologic features. Gene expression assays have the potential to supplement what were previously a few distinct features with many thousands of features. We have developed Bayesian regression models that provide predictive capability based on gene expression data derived from DNA microarray analysis of a series of primary breast cancer samples. These patterns have the capacity to discriminate breast tumors on the basis of estrogen receptor status and also on the categorized lymph node status. Importantly, we assess the utility and validity of such models in predicting the status of tumors in crossvalidation determinations. The practical value of such approaches relies on the ability not only to assess relative probabilities of clinical outcomes for future samples but also to provide an honest assessment of the uncertainties associated with such predictive classifications on the basis of the selection of gene subsets for each validation analysis. This latter point is of critical importance in the ability to apply these methodologies to clinical assessment of tumor phenotype.
We have used high-density DNA microarrays to provide an analysis of gene regulation during the mammalian cell cycle and the role of E2F in this process. Cell cycle analysis was facilitated by a combined examination of gene control in serum-stimulated fibroblasts and cells synchronized at G 1 /S by hydroxyurea block that were then released to proceed through the cell cycle. The latter approach (G 1 /S synchronization) is critical for rigorously maintaining cell synchrony for unambiguous analysis of gene regulation in later stages of the cell cycle. Analysis of these samples identified seven distinct clusters of genes that exhibit unique patterns of expression. Genes tend to cluster within these groups based on common function and the time during the cell cycle that the activity is required. Placed in this context, the analysis of genes induced by E2F proteins identified genes or expressed sequence tags not previously described as regulated by E2F proteins; surprisingly, many of these encode proteins known to function during mitosis. A comparison of the E2F-induced genes with the patterns of cell growth-regulated gene expression revealed that virtually all of the E2F-induced genes are found in only two of the cell cycle clusters; one group was regulated at G 1 /S, and the second group, which included the mitotic activities, was regulated at G 2 . The activation of the G 2 genes suggests a broader role for E2F in the control of both DNA replication and mitotic activities.Rapid progress has been made in the understanding of regulatory pathways that govern the transition of cells from a quiescent state into a cell cycle. Such studies have highlighted the critical role of the signaling pathway that involves the accumulation of D cyclin/cdk4 activity leading to the phosphorylation of the retinoblastoma protein, which then allows an accumulation of E2F transcription activity (21,24). A variety of experiments have demonstrated the role of E2F proteins in the control of expression of genes important for DNA replication as well as further cell cycle progression (5, 18). In particular, E2F activity is responsible for the activation of genes encoding DNA replication proteins, enzymes responsible for deoxynucleotide biosynthesis, proteins that assemble to form functional origin complexes, and kinases that are involved in the activation of initiation.Although much has been learned from these studies of E2F transcription control, important questions remain. For one, the scope of the gene-regulatory control by E2F proteins has not been addressed. In large part, the identification of target genes has followed from the initial studies of the DNA tumor virus oncoproteins, such as adenovirus E1A and simian virus 40 T antigen; previous work demonstrated that these proteins were capable of inducing quiescent cells to enter S phase, and associated with this induction was an activation of various genes encoding DNA replication activities (17). This activity coincides with an ability to inactivate the Rb tumor suppressor protein and thus...
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