Our working hypothesis focuses on the convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment for therapeutic targeting and monitoring. We continue to examine two pathways we identified: the BAG-3 stress co-chaperone protein and the ovarian cancer growth and survival factor and its partner, progranulin (pgrn) and secretory leukocyte protease inhibitor (SLPI). Element 1) BAG3 causes a gain-of-function action in survival and proliferation. We have identified a functional role for the WW domain of BAG3 in the proper regulation of actin organization during G2/M;these findings put BAG3 in the cell cycle as both a regulator and a subject of cell cycle regulation. Disruption of WW domain-specific events results in polynucleation and dysfunctional actin nucleation. New partner protein interactions necessary for proper cytokinesis have been identified and their effects on cell cycle are under study. Further, this domain, wholly encoded in exon 1, is genomically 18MB upstream of subsequent exons in a gene poor region of chromosome 10. Functional effects of forced huBAG3 expression in MMTV-BAG3 transgenic mice have uncovered gain-of-function effects with excessive events during mammary gland maturation and improper involution upon pup withdrawl from nursing females. Characterization is ongoing to determine potential underlying mechanism. Hyperplastic nodules (HAN) are seen both developing transgenic mice and in those exposed to DMBA where we also see some malignant tumor development selectively in the virgin transgenic mice. Malignant lesions are ductal and ER+. Cytokeratin and hormone receptor staining confirmed the luminal ductal origin. Repeat pregnancy experiments did not result in tumors in the BAG3 heterozygotes, and did not alter tumorigenesis in heterozygous crosses to WAP/INT3 mice with Dr. Smith MBTL, CCR. 2) The progranulin/SLPI axis promotes EMT and invasion. Our studies of pgrn and its partner protein, SLPI, have continued. Increased dissemination in vivo of HEY-A8 cells overexpressing SLPI and SLPI mutants was observed and is independent of loss of protease inhibition function. The requirement for PGRN interaction is also found in HaCaT keratinocyte EMT experiments. These cells were selected in order to remove the proliferative drive of SLPI and allowed the separation of the pro-invasive and EMT-like behavior of SLPI and mutants. SLPI collaborates with TGFbeta to augment invasive potential of HaCaT cells;this is altered in the mutants that cannot bind pgrn and completely abrogated when pgrn is silenced.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Clinical Sciences
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Han, Jasmine J; Yu, Minshu; Houston, Nicole et al. (2011) Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers. Gynecol Oncol 120:5-10
Kassis, Jareer N; Virador, Victoria M; Guancial, Elizabeth A et al. (2009) Genomic and phenotypic analysis reveals a key role for CCN1 (CYR61) in BAG3-modulated adhesion and invasion. J Pathol 218:495-504
Virador, Victoria M; Davidson, Ben; Czechowicz, Josephine et al. (2009) The anti-apoptotic activity of BAG3 is restricted by caspases and the proteasome. PLoS One 4:e5136
Elstrand, Mari Bunkholt; Kleinberg, Lilach; Kohn, Elise C et al. (2009) Expression and clinical role of antiapoptotic proteins of the bag, heat shock, and Bcl-2 families in effusions, primary tumors, and solid metastases in ovarian carcinoma. Int J Gynecol Pathol 28:211-21
Simpkins, Fiona A; Devoogdt, Nick M; Rasool, Nabila et al. (2008) The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells. Carcinogenesis 29:466-72