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). 1) BAG3 causes a gain-of-function action in survival and proliferation. New findings have identified a functional role for the WW domain of BAG3;these findings put BAG3 in the cell cycle as both a regulator and a subject of cell cycle regulation. While not disruptive to the cell cycle as a full protein, disruption of domain-specific events alters proper cell cycle flow and results in polynucleation. New partner protein interactions necessary for proper cytokinesis have been identified and may lead to novel translational directions. Collaborations for genetic and proteomic effects on BAG3 are ongoing. 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 the underlying cause. The hyperplasia and tumors in the DMBA carcinogenesis experiment in virgin mice are under study. Lesions are increased in transgenic mice but are not universal, and are ductal in nature. Cytokeratin and hormone receptor staining are ongoing to classify the lesion types. Repeat pregnancy experiments are ongoing to examine the role of the MMTV activation of huBAG3 expression and carcinogenic potential, and crosses to WAP/INT3 mice are ongoing with Dr. Smith of the MBTL, CCR. Genomic characterization of the BAG3 locus has begun. TCGA databases are being examined as this gene-poor region houses a potential amplicon. Dr. McCollum, a senior postdoctoral fellow in our group received peer-reviewed funding from the Kaleidoscope of Hope Foundation with which to prosecute this hypothesis. 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 its mutants was observed and is independent of loss of protease inhibition function. Repeat xenografts including the pgrn binding domain mutants indicate a requirement for pgrn binding by SLPI. Expression array data are pending from the HeyA8 SLPI mutant series. The requirement for PGRN interaction is also found in the HaCaT keratinocyte EMT experiments. SLPI collaborates with TGFbeta to augment invasive potential of HaCaT cells in a pgrn-dependent fashion. New studies are further dissecting the interaction of pgrn and SLPI in cancer promotion. We plan to take this portfolio of activity, including the collaborative anti-SLPI augmentation of paclitaxel xenograft findings forward for translation to the clinic. We continue to collaborate with Dr. Annunziata in her investigations of the NKFB pathways in womens cancers. MMP-9, shown by us to be regulated and activated by SLPI, is in the NFKB IKKB gene signature and there is relationships to SLPI as well. Planning for these projects is underway.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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