In spite of the number of studies that have been conducted, the role of elevated cyclooxygenase (COX)-2 (and its prostaglandin (PG) products) in skin tumor development remains elusive. Several observations suggest a contributory role, including a reduction in skin tumors following an initiation-promotion protocol in either COX-1 or COX-2 knockout mice, and that application of COX inhibitory non-steroidal anti-inflammatory drugs (NSAIDs) usually reduce skin carcinogenesis. We and others, however, have shown that for several cell types NSAIDs induce apoptosis through PG-independent mechanisms, suggesting that this pharmacological approach is not informative with regard to understanding the involvement of PGs in carcinogenesis. To more directly assess the role of COX-2, we took the genetic approach of generating transgenic mice in which COX-2 was overexpressed through the use of a keratin-14 (K14) promoter. These mice are almost completely resistant to phorbol ester promotion. In earlier studies, the topical application of PGE2, but not PGF2alpha, inhibited phorbol ester promotion. Collectively these studies indicate the contribution of COX-2 to skin carcinogenesis is incompletely understood. It is hypothesized that upregulated COX- 2 represses the development of skin tumors through the generation of high levels of PGE2. This hypothesis will be tested by answering the following questions: (1) Is the inhibitory effect of COX-2 overexpression stage-specific or tumor-promoter-specific? Inducible COX-2 transgenic mice will be generated and COX-2 turned on or off at specified times during tumor development. (2) Do specific PGs have inhibitory effects on promotion? Does cAMP mimic this effect? First, PGE2, PGF2? or PGD2 will be applied topically at the time of phorbol ester treatment during promotion of wild-type mice. Second, the role of cAMP will be assessed with regard to its ability to interfere with signaling from PKC and its ability to inhibit tumor promotion. (3) What is the basis for the resistance to tumor promotion in the K14.COX-2 transgenics? 2-D gel electrophoresis and mass spec will to be used to identify changes in protein expression in K14.COX-2 transgenic skin. The function of one of the proteins found to be upregulated in K14.COX-2 mice, galectin-7, which has been implicated in apoptosis, and other candidate proteins will be determined using transient transfection and the significance of candidate proteins assessed with regard to markers for tumor development, including proliferation, apoptosis and invasion.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100140-05
Application #
7234035
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Poland, Alan P
Project Start
2003-06-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2010-05-31
Support Year
5
Fiscal Year
2007
Total Cost
$318,565
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Surh, Inok; Rundhaug, Joyce E; Pavone, Amy et al. (2012) The EP1 receptor for prostaglandin E2 promotes the development and progression of malignant murine skin tumors. Mol Carcinog 51:553-64
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Surh, Inok; Rundhaug, Joyce; Pavone, Amy et al. (2011) Upregulation of the EP1 receptor for prostaglandin E2 promotes skin tumor progression. Mol Carcinog 50:458-68
Rundhaug, Joyce E; Fischer, Susan M (2010) Molecular Mechanisms of Mouse Skin Tumor Promotion. Cancers (Basel) 2:436-482
Ishikawa, Tomo-O; Kumar, Indracanti Prem; Machado, Hidevaldo B et al. (2010) Positron emission tomography imaging of DMBA/TPA mouse skin multi-step tumorigenesis. Mol Oncol 4:119-25
Shen, Jianjun; Fischer, Susan M (2010) Molecular profiling of the epidermis: a proteomics approach. Methods Mol Biol 585:225-52
Wang, Xingya; Colby, Jennifer K L; Rengel, Robert C et al. (2009) Overexpression of cyclooxygenase-2 (COX-2) in the mouse urinary bladder induces the expression of immune- and cell proliferation-related genes. Mol Carcinog 48:1-13
Ansari, Kausar M; Rundhaug, Joyce E; Fischer, Susan M (2008) Multiple signaling pathways are responsible for prostaglandin E2-induced murine keratinocyte proliferation. Mol Cancer Res 6:1003-16

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