The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone modifying complexes to chromatin. Here, global profiling of CtBP in breast cancer cells reveals that it drives epithelial to mesenchymal transition, stem cell pathways, and genome instability. CtBP expression induces mesenchymal and stem cell-like features while CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively down-regulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumors predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer.

Previous work identified the Rap1 GTPase-activating protein Sipa1 as a germ-line-encoded metastasis modifier. The bromodomain protein Brd4 physically interacts with and modulates the enzymatic activity of Sipa1. In vitro analysis of a highly metastatic mouse mammary tumor cell line ectopically expressing Brd4 demonstrates significant reduction of invasiveness without altering intrinsic growth rate. However, a dramatic reduction of tumor growth and pulmonary metastasis was observed after s.c. implantation into mice, implying that activation of Brd4 may somehow be manipulating response to tumor microenvironment in the in vivo setting. Further in vitro analysis shows that Brd4 modulates extracellular matrix gene expression, a class of genes frequently present in metastasis-predictive gene signatures. Microarray analysis of the mammary tumor cell lines identified a Brd4 activation signature that robustly predicted progression and/or survival in multiple human breast cancer datasets analyzed on different microarray platforms. Intriguingly, the Brd4 signature also almost perfectly matches a molecular classifier of low-grade tumors. Taken together, these data suggest that dysregulation of Brd4-associated pathways may play an important role in breast cancer progression and underlies multiple common prognostic signatures.gene expression signatures ͉ metastasis ͉ mouse models T he majority of deaths attributable to solid cancers result from the pathophysiological impact of metastasis. This is starkly illustrated when one considers that the median survival of patients with metastatic breast cancer is Ϸ2-4 years (1), compared with an Ϸ80% survival rate for women whose disease remains nonmetastatic. Advanced disseminated breast cancer thus remains an incurable condition regardless of new treatments (2). It is therefore important to develop a comprehensive understanding of the metastasis biology to identify patients at higher risk of tumor dissemination. This in turn may permit development of therapies and initiation of more aggressive treatment in women with poorer prognoses to reduce the incidence and extent of metastatic disease. Conversely, it may also prove possible to identify women at low risk of metastasis, thus sparing them needless adjuvant therapy.Our laboratory has demonstrated that germ-line genetic variation influences tumor progression. Specifically, in a model system, the F 1 progeny of the highly metastatic polyoma middle-T (PyMT) transgenic mouse and different inbred laboratory mouse strains display wide variations in metastatic efficiency after mammary tumor development (3). The most likely explanation for this observation is that germ-line variation modulates tumor progression. Subsequent identification of heritable loci modulating metastatic efficiency support this hypothesis (4, 5). Positional cloning subsequently identified Sipa1, a GTPase activating protein (GAP) that negatively regulates Rap-GTPases, as the first polymorphic metastasis efficiency gene in mice (6). Studies of human cancer have suggeste...

Purpose Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with poor prognosis. Understanding molecular changes in ESCC will enable identification of molecular subtypes and provide potential targets for early detection and therapy. Experimental Design We followed up a previous array study with additional discovery and confirmatory studies in new ESCC cases using alternative methods. We profiled global gene expression for discovery and confirmation, and validated selected dysregulated genes with additional RNA and protein studies. Results A total of 159 genes showed differences with extreme statistical significance (P