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Osteoprotegerin in breast cancer cells: role in tumor growth and metastasis

Award Number: R15CA161486
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2012
PERIOD OF PERFORMANCE END DATE: 08/31/2016

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Osteoprotegerin in breast cancer cells: role in tumor growth and metastasis - DESCRIPTION (provided by applicant): The goal of this study is to investigate tumor promoting effects of the secreted protein osteoprotegerin (OPG). OPG expression by human breast cancer cell lines in vitro inhibits TNF- related apoptosis inducing ligand (TRAIL)-mediated cell death. Breast cancer cells may produce OPG to block effects of TRAIL and resist being killed. Our preliminary data suggests OPG also promotes metastasis. The current study will investigate regulation of OPG expression in breast cancer cells, the impact of OPG on metastasis and the mechanisms whereby OPG impacts tumor cell behavior. Data generated will reveal whether OPG inhibitors should be developed as a therapy for breast cancer. Our preliminary data links OPG expression with nuclear factor kappa B (NF-?B) activity. This link will be investigated to determine if OPG mediates tumor promoting effects of NF-?B. Human breast cancer cells will be treated with NF-?B inhibitors and effects on OPG mRNA and protein expression measured. To study OPG in vivo, human breast cancer cell lines will be treated with shRNA to knockdown OPG or non-coding shRNA to generate control cells. These cells will then be used to investigate the consequences of OPG knockdown on metastasis in the chick embryo metastasis model. The chick embryo model recapitulates the stages of metastasis observed in human tumors and represents a rapid way to gain data regarding molecular factors that promote tumorigenesis. Cells will either be introduced directly onto the chick chorioallantoic membrane to allow primary tumor formation and metastasis or injected IV to specifically study metastasis. After one week incubation, metastasis of human breast cancer cells to chick tissues can be measured by real time PCR for human DNA. These studies will be performed in the presence and absence of TRAIL to reveal whether inhibition of OPG sensitizes cells to TRAIL-mediated cell death and/or if a lack of OPG reduces metastasis independent of its interaction with TRAIL. To determine the mechanism whereby OPG impacts metastasis, primary tumors from the chick model will be analyzed for changes in the expression of genes that would result in a tumor promoting effect. In addition in vitro assays will be performed to determine the impact of OPG knockdown on apoptosis, proliferation, migration and invasion in the presence and absence of TRAIL and also Receptor Activator of Nuclear Factor-kappaB ligand (RANKL), the other molecule known to bind OPG. This will allow us to determine the effect of OPG on tumor behavior in the presence of both of its characterized ligands. This study is of relevance to publi health as it will provide evidence that treatment strategies to block OPG could be used in combination with TRAIL or other types of breast cancer therapy to prevent metastasis, improve prognosis and increase survival in breast cancer patients. PUBLIC HEALTH RELEVANCE: The current application will investigate the hypothesis that the production of the protein osteoprotegerin (OPG) by breast cancer cells promotes tumor progression and metastasis. This will demonstrate whether OPG represents a molecule that could be blocked as part of targeted treatment for breast cancer. Since many patients do not respond or become resistant to current targeted therapies then identification of new therapeutic targets such as OPG will increase treatment options and improve prognosis for breast cancer patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2017 ( Subtotal = -$539 )
2017	2012	UNIVERSITY OF HAWAII SYSTEMS	200 W KAWILI ST	HILO	HI	96720	HAWAII	USA	Cancer Biology Research	000	1	1/19/2017	NEW	-$539
														Subtotal = -$539

Issue Date FY: 2012 ( Subtotal = $410,100 )
2012	2012	UNIVERSITY OF HAWAII	2530 Dole St., Sakamaki D200	HONOLULU	HI	96822	HONOLULU	USA	Cancer Biology Research	000	1	8/27/2012	NEW	$410,100
														Subtotal = $410,100

Grand Total All Awards = $409,561

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Osteoprotegerin in breast cancer cells: role in tumor growth and metastasis

Award Number: R15CA161486

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2012

PERIOD OF PERFORMANCE END DATE: 08/31/2016

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