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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC009163-26
Application #
8763690
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2013
Total Cost
$244,636
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Yu, Minshu; Henning, Ryan; Walker, Amanda et al. (2012) L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer. J Cell Mol Med 16:2369-78
Kim, Geoffrey; Davidson, Ben; Henning, Ryan et al. (2012) Adhesion molecule protein signature in ovarian cancer effusions is prognostic of patient outcome. Cancer 118:1543-53
Kamrava, Mitchell; Gius, David; Casagrande, Giovanna et al. (2011) Will targeting insulin growth factor help us or hurt us?: An oncologist's perspective. Ageing Res Rev 10:62-70
Hoskins, Ebony; Rodriguez-Canales, Jaime; Hewitt, Stephen M et al. (2011) Paracrine SLPI secretion upregulates MMP-9 transcription and secretion in ovarian cancer cells. Gynecol Oncol 122:656-62
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
McCollum, Andrea K; Casagrande, Giovanna; Kohn, Elise C (2010) Caught in the middle: the role of Bag3 in disease. Biochem J 425:e1-3
Annunziata, Christina M; Stavnes, Helene Tuft; Kleinberg, Lilach et al. (2010) Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Cancer 116:3276-84
Rasool, Nabila; LaRochelle, William; Zhong, Haihong et al. (2010) Secretory leukocyte protease inhibitor antagonizes paclitaxel in ovarian cancer cells. Clin Cancer Res 16:600-9
He, Yuanzheng; Blackford Jr, John A; Kohn, Elise C et al. (2010) STAMP alters the growth of transformed and ovarian cancer cells. BMC Cancer 10:128
Hernandez, Lidia; Hsu, Sarah C; Davidson, Ben et al. (2010) Activation of NF-kappaB signaling by inhibitor of NF-kappaB kinase beta increases aggressiveness of ovarian cancer. Cancer Res 70:4005-14

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