DEK activitites in epithelial cancers
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death among women in the United States. Despite efforts to increase awareness and develop novel treatments, there is still much to learn about the molecular etiology of breast cancer. Therefore, it is important to characterize novel breast-cancer related proteins that may be used for diagnosis, prognosis, and as markers for the best course of treatment. Our research indicates that the DEK oncogene may be a novel breast cancer-related gene important in regulating the development and progression of breast cancer. First, we have found that the DEK protein is over-expressed in primary and cultured breast cancers compared to immortalized and normal asmples. Using primary breast cancers from patients, we have also discovered that DEK expression correlates with the presence of steroid hormone receptors, including estrogen, progesterone, and androgen receptors, which are critically important when deciding how to treat the patient. Using cultured breast cancer cell lines as a model, we have characterized DEK as an oncogene using several methods. First, over-expression of DEK in non-tumorigenic mammary epithelial cells resulted in increased growth rates and motility. Second, decreased expression of DEK via RNAi in two breast cancer cell lines resulted in decreased growth rates, motility, and invasion, and impaired growth in nude mice. Current studies will determine the role of DEK in breast cancer development in vivo. In addition, we continue to explore the correlation between DEK and hormone receptor signaling as well as the molecular mechanism(s) by which DEK controls the growth of mammary epithelial cells.
A role for DEK in the DNA damage response and tumorigenesis
Our laboratory studies human papillomaviruses (HPVs) and associated human cancers. Two HPV oncogenes, E6 and E7, are known to drive epithelial cancer through inactivation of cellular tumor suppressors, such as p53 and Rb. Gina’s project focuses on the chromatin binding protein DEK, which is upregulated by the HPV E7 protein, and is a cellular oncogene that is transcriptionally induced in many human cancers. We have shown that DEK overexpression extends the life span of primary keratinocytes and inhibits both cellular senescence and apoptosis. Conversely, the specific depletion of DEK in proliferating cells results in genomic instability and subsequent induction of cell death in vitro and in vivo. This phenotype is most dramatic in rapidly dividing cancer cells, less dramatic in primary cells and not observed in differentiated cells. Together with the finding that DEK knockout mice exhibit increased resistance to chemically induced skin tumorigenesis, we hypothesize that DEK inhibition may be useful for the treatment of cancer. Gina’s current project seeks to link DEK-dependent DNA damage responses with a functional role for this protein in tumorigenesis in vivo.
