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FURIN AND THE ETIOPATHOGENESIS OF UV-INDUCED SKIN CANCER

Award Number: R01CA133001
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2009
PERIOD OF PERFORMANCE END DATE: 02/28/2013

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FURIN AND THE ETIOPATHOGENESIS OF UV-INDUCED SKIN CANCER - DESCRIPTION (provided by applicant): Furin is a protein processing enzyme of the family of proprotein convertases (PCs), which has a significant role in cancer etiopathogenesis. In this application, we propose to investigate the function of furin during skin tumor development, focusing on the early and late changes that take place after UV exposure of the mouse skin. PACE4, another related PC, has been shown to have a role in murine tumor cell invasiveness by activating relevant proteases. Furin is also able to enhance cell proliferation in human precancerous and cancer cells by activating growth factor and growth factor receptors, such as IGF-R1. The lack of a mouse model to study the function of furin during carcinogenesis prompted us to design a series of experiments using transgenic mice to facilitate the better understanding of this prominent PC in the etiopathogenesis of skin cancer. Our objective in this proposal is to determine the mechanisms by which furin contributes to tumor development alone or in combination with PACE4 using transgenic mice overexpressing PCs. Two aims have been designed to this effect: First we will determine if the targeted in vivo overexpression of furin alone will enhance the development of experimental skin cancer induced by UV. We shall investigate the simultaneous in vivo overexpression of PACE4 and furin using bigenic mice in order to establish the possible cooperation of the 2 PCs in skin carcinogenesis. Substrate- specificity will be evaluated in keratinocyte cultures derived from monogenic (K5-PACE4 and K5-Furin) as well as from bigenic mice (K5-PACE4/Furin). These experiments will clarify the significance of furin's pro-proliferative effect and whether its pro-invasive effects are the same or different from PACE4's predominant pro-invasive function. In addition, this specific aim will determine whether the combination of both PCs have an enhancing effect on any or both of these biological processes. Second, we will also determine if PC inhibition blocks tumor growth and development in transgenic models. Crossing monogenic PC transgenic mice as well as double transgenics K5-Furin/PACE4 with K5-PDX and K5-PC-Propeptide transgenic mice expressing either the cDNA of a competitive PC peptide inhibitor or that of the physiological inhibitors of PCs, we will determine if inhibition of PCs alters the formation of skin tumors induced by UV carcinogenesis. PUBLIC HEALTH RELEVANCE: This application will use modern experimental animal models to dissect the function of proprotein convertases, enzymes that activate relevant cancer-associated biomolecules, during the early formation and growth of squamous cell carcinomas, one of the most common cancers of the human skin. The proposed studies will lead to the identification of mechanisms involved in the origination of cancer that could be of great practical value in its early diagnosis and treatment.


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: 2012 ( Subtotal = $358,605 )
2012	2012	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	4	3/15/2012	NON-COMPETING CONTINUATION	$358,605
														Subtotal = $358,605

Issue Date FY: 2011 ( Subtotal = $351,225 )
2011	2011	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	3	5/13/2011	NON-COMPETING CONTINUATION	$25,346
2011	2011	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	3	1/11/2011	NON-COMPETING CONTINUATION	$325,879
														Subtotal = $351,225

Issue Date FY: 2010 ( Subtotal = $362,088 )
2010	2010	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	2	2/11/2010	NON-COMPETING CONTINUATION	-$362,088
2010	2010	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	002	2	2/16/2010	NON-COMPETING CONTINUATION	$362,088
2010	2010	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	2	1/29/2010	NON-COMPETING CONTINUATION	$362,088
														Subtotal = $362,088

Issue Date FY: 2009 ( Subtotal = $361,569 )
2009	2009	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	1	3/25/2009	NEW	$361,569
														Subtotal = $361,569

Grand Total All Awards = $1,433,487

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FURIN AND THE ETIOPATHOGENESIS OF UV-INDUCED SKIN CANCER

Award Number: R01CA133001

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2009

PERIOD OF PERFORMANCE END DATE: 02/28/2013

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