Disease progression and recurrence are major barriers to surviving breast cancer. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly over-expressed breast cancer oncogenes, Ron and DEK, cooperate to promote advanced disease through multi-pronged effects on β-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron over-expression in human disease stimulates β-catenin nuclear translocation and is an independent predictor of metastatic dissemination. Dek is a chromatin-associated oncogene whose expression has been linked to cancer through multiple mechanisms, including β-catenin activity. We demonstrate here that Dek is a downstream target of Ron receptor activation in murine and human models. The absence of Dek in the MMTV-Ron mouse model led to a significant delay in tumor development, characterized by decreased cell proliferation, diminished metastasis, and fewer cells expressing cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion in vitro and in vivo. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical β-catenin signaling loop. Finally, we show that Dek over-expression promotes tumorigenic phenotypes in immortalized human mammary epithelial MCF10A cells and, in the context of Ron receptor activation, correlates with disease recurrence and metastasis in patients. Overall, our studies demonstrate that DEK over-expression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/β-catenin signaling.

There is a long-standing correlation between inflammation, inflammatory cell signaling pathways, and tumor formation. Understanding the mechanisms behind inflammation-driven tumorigenesis is of great research and clinical importance. Although not entirely understood, these mechanisms include a complex interaction between the immune system and the damaged epithelium that is mediated by an array of molecular signals of inflammation—including reactive oxygen species (ROS), cytokines, and NFκB signaling—that are also oncogenic. Here, we discuss the association of the unique DEK protein with these processes. Specifically, we address the role of DEK in chronic inflammation via viral infections and autoimmune diseases, the overexpression and oncogenic activity of DEK in cancers, and DEK-mediated regulation of NFκB signaling. Combined, evidence suggests that DEK may play a complex, multidimensional role in chronic inflammation and subsequent tumorigenesis.

SUMMARY During development, progenitors often differentiate many cell generations after receiving signals. These delays must be robust yet tunable for precise population size control. Polycomb repressive mechanisms, involving histone H3 lysine-27 trimethylation (H3K27me3), restrain the expression of lineage-specifying genes in progenitors and may delay their activation and ensuing differentiation. Here, we elucidate an epigenetic switch controlling the T cell commitment gene Bcl11b that holds its locus in a heritable inactive state for multiple cell generations before activation. Integrating experiments and modeling, we identify a mechanism where H3K27me3 levels at Bcl11b , regulated by methyltransferase and demethylase activities, set the time delay at which the locus switches from a compacted, silent state to an extended, active state. This activation delay robustly spans many cell generations, is tunable by chromatin modifiers and transcription factors, and is independent of cell division. With their regulatory flexibility, such timed epigenetic switches may broadly control timing in development.

DEK, a chromatin-remodeling gene expressed in most human tissues, is known for its role in cancer biology and autoimmune diseases. DEK depletion in vitro reduces cellular proliferation, induces DNA damage subsequently leading to apoptosis, and down-regulates canonical Wnt/β-catenin signaling, a molecular pathway essential for learning and memory. Despite a recognized role in cancer (non-neuronal) cells, DEK expression and function is not well characterized in the central nervous system. We conducted a gene ontology analysis (ToppGene), using a cancer database to identify genes associated with DEK deficiency, which pinpointed several genes associated with cognitive-related diseases (i.e., Alzheimer’s disease, presenile dementia). Based on this information, we examined DEK expression in corticolimbic structures associated with learning and memory in adult male and female mice using immunohistochemistry. DEK was expressed throughout the brain in both sexes, including the medial prefrontal cortex (prelimbic, infralimbic and dorsal peduncular). DEK was also abundant in all amygdalar subdivisions (basolateral, central and medial) and in the hippocampus including the CA1, CA2, CA3, dentate gyrus (DG), ventral subiculum and entorhinal cortex. Of note, compared to males, females had significantly higher DEK immunoreactivity in the CA1, indicating a sex difference in this region. DEK was co-expressed with neuronal and microglial markers in the CA1 and DG, whereas only a small percentage of DEK cells were in apposition to astrocytes in these areas. Given the reported inverse cellular and molecular profiles (e.g., cell survival, Wnt pathway) between cancer and Alzheimer’s disease, these findings suggest a potentially important role of DEK in cognition.

Upon Ag exposure, naive B cells expressing BCR able to bind Ag can undergo robust proliferation and differentiation that can result in the production of Ab-secreting and memory B cells. The factors determining whether an individual naive B cell will proliferate following Ag encounter remains unclear. In this study, we found that polyclonal naive murine B cell populations specific for a variety of foreign Ags express high levels of the orphan nuclear receptor Nur77, which is known to be upregulated downstream of BCR signaling as a result of cross-reactivity with self-antigens in vivo. Similarly, a fraction of naive human B cells specific for clinically-relevant Ags derived from respiratory syncytial virus and HIV-1 also exhibited an IgMLOW IgD+ phenotype, which is associated with self-antigen cross-reactivity. Functionally, naive B cells expressing moderate levels of Nur77 are most likely to proliferate in vivo following Ag injection. Together, our data indicate that BCR cross-reactivity with self-antigen is a common feature of populations of naive B cells specific for foreign Ags and a moderate level of cross-reactivity primes individual cells for optimal proliferative responses following Ag exposure.