? Exposure to ultraviolet (UV) light is the major etiologic event for cutaneous squamous and basal cell carcinomas in humans and is also a risk factor for melanoma. The molecular pathways responsible for UV irradiation-induced tumors involve genetic and epigenetic events. While initiation events are generally irreversible, at least some of the processes associated with promotion and progression can be effectively inhibited or reversed, leading to a reduction in tumor incidence and severity. The goal of the proposed study is to determine the relative importance of each of three processes and pathways, i.e., proliferation, survival and/or inflammation/angiogenesis on the development of squamous cell carcinoma. We propose to identify the key signaling molecules and pathways that control each of these processes and determine which is more important, through use of genetic manipulation of the UV-sensitive SKH-1 hairless mouse. Available evidence indicates that cell cycle processes and cell survival can be regulated by the NFkB pathway, the Akt pathway, the stat3 pathway, and the Rb-E2F1 pathway while inflammation is regulated by the NFkB pathway, thus these pathways may control critical processes in cancer development. The goal of this study will be approached through answering the following questions: 1) How important is cell survival to skin cancer? 2) How important is inflammation and angiogenesis to skin cancer? 3) How important are alterations in the expression of cell cycle genes to skin cancer? These questions will be addressed through the use of existing mouse models, or where needed, through the development of new models. These models will also be made available to other investigators for their studies of pathways and UV carcinogenesis.
The specific aims of this comprehensive Project are: (1) Transfer existing genetic modifications relating to proliferation, apoptosis and inflammation/angiogenesis onto the SKH-1 hairless background, the most useful strain for UV carcinogenesis studies. This includes transgenes for stat3, Akt, VEGF and Cre, and deficiencies (knockout) for cyclin D1, cdk4, E2F1, Rb, stat3, Bcl-xL, VEGF and IL-1R1. This will be done using the speed congenic approach. (2) Create needed new SKH-1 hairless models using inducible systems. Targeted inducible transgenics (Bcl2, Bcl-xL, FasL, NFkB(p50), IL-la and inducible conditional transgenics (Akt, FasL, Bcl2 and NFkB(p50), will made using gene switch approaches. (3) Where indicated, models with multiple genetic alterations will be developed. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA105345-01
Application #
6729532
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Marks, Cheryl L
Project Start
2004-09-14
Project End
2009-03-31
Budget Start
2004-09-14
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$850,000
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Chari, N S; Romano, R A; Koster, M I et al. (2013) Interaction between the TP63 and SHH pathways is an important determinant of epidermal homeostasis. Cell Death Differ 20:1080-8
Guo, Ruifeng; Chen, Jie; Mitchell, David L et al. (2011) GCN5 and E2F1 stimulate nucleotide excision repair by promoting H3K9 acetylation at sites of damage. Nucleic Acids Res 39:1390-7
Park, Eunmi; Liu, Bigang; Xia, Xiaojun et al. (2011) Role of IKK? in skin squamous cell carcinomas. Future Oncol 7:123-34
Liu, B; Willette-Brown, J; Liu, S et al. (2011) IKK? represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin. Cell Death Differ 18:1854-64
Kim, Dae Joon; Tremblay, Michel L; Digiovanni, John (2010) Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation. PLoS One 5:e10290
Xia, Xiaojun; Park, Eunmi; Liu, Bigang et al. (2010) Reduction of IKKalpha expression promotes chronic ultraviolet B exposure-induced skin inflammation and carcinogenesis. Am J Pathol 176:2500-8
Guo, Ruifeng; Chen, Jie; Zhu, Feng et al. (2010) E2F1 localizes to sites of UV-induced DNA damage to enhance nucleotide excision repair. J Biol Chem 285:19308-15
Kim, Dae Joon; Kataoka, Ken; Sano, Shigetoshi et al. (2009) Targeted disruption of Bcl-xL in mouse keratinocytes inhibits both UVB- and chemically induced skin carcinogenesis. Mol Carcinog 48:873-85
Kim, D J; Angel, J M; Sano, S et al. (2009) Constitutive activation and targeted disruption of signal transducer and activator of transcription 3 (Stat3) in mouse epidermis reveal its critical role in UVB-induced skin carcinogenesis. Oncogene 28:950-60
Rojas, Paola; Benavides, Fernando; Blando, Jorge et al. (2009) Enhanced skin carcinogenesis and lack of thymus hyperplasia in transgenic mice expressing human cyclin D1b (CCND1b). Mol Carcinog 48:508-16

Showing the most recent 10 out of 36 publications