Breast cancer is 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 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. The human DEK gene was first identified as a fusion with the CAN/NUP214 nucleoporin gene in AML patients. It is ubiquitously expressed, chromatin-binding protein in proliferating cells with potential roles in transcriptional regulation, DNA topology, replication, and repair. As a proto-oncogene, DEK inhibits cellular senescence, differentiation, and apoptosis in primary keratinocytes and in cervical cancer cells, presumably through regulation of the p53 protein family. However, its oncogenic activities in vivo remain poorly understood. Gene amplification and upregulated mRNA expression have been described for the human DEK gene in hematopoietic cancers and solid tumors. Meta-analysis using Oncomine and my preliminary data indicated that it also may be important for breast cancer pathogenesis: DEK mRNA and protein overexpression was observed in primary and cultured breast cancers compared to normal mammary tissue, and overexpression strongly correlated with several clinico-pathological variables. DEK protein expression and potential oncogenic activity have not been studied in most cancers, including breast cancer. My preliminary data suggest that DEK may influence DNA repair via the repression of ATM. Based on our data, I hypothesize that DEK is involved in breast cancer development through interference with cell cycle checkpoints and DNA damage response pathways.
Three specific aims are proposed to test this hypothesis: (1) Determine whether DEK expression is elevated in murine and human primary breast cancer specimens and cultured cell lines;(2) Determine if DEK upregulation stimulates tumor phenotypes in cell culture and xenograft models of breast cancer;and (3) Delineate the role of DEK in breast cancer development in vivo.

Public Health Relevance

These experiments will determine the role of DEK in the initiation and progression of breast cancer, and will generate a murine model system to support future preclinical studies. Recent data from our laboratory support the targeting of DEK as a potential clinical approach with the finding that the rate of cellular proliferation directly correlates with the degree of cell death following DEK depletion: differentiated cells are not susceptible, whereas rapidly proliferating tumor cells undergo dramatic cell death. We hypothesize that the targeting of DEK in breast cancer may be of therapeutic value.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA139931-02
Application #
7928091
Study Section
Special Emphasis Panel (ZRG1-F09-B (20))
Program Officer
Jakowlew, Sonia B
Project Start
2009-09-15
Project End
2011-09-14
Budget Start
2010-09-15
Budget End
2011-09-14
Support Year
2
Fiscal Year
2010
Total Cost
$50,474
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Privette Vinnedge, L M; Benight, N M; Wagh, P K et al. (2015) The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers. Oncogene 34:2325-36
Privette Vinnedge, Lisa M; Kappes, Ferdinand; Nassar, Nicolas et al. (2013) Stacking the DEK: from chromatin topology to cancer stem cells. Cell Cycle 12:51-66
Privette Vinnedge, Lisa M; Ho, Shuk-Mei; Wikenheiser-Brokamp, Kathryn A et al. (2012) The DEK oncogene is a target of steroid hormone receptor signaling in breast cancer. PLoS One 7:e46985
Privette Vinnedge, L M; McClaine, R; Wagh, P K et al. (2011) The human DEK oncogene stimulates ?-catenin signaling, invasion and mammosphere formation in breast cancer. Oncogene 30:2741-52