Tumors of several sites in human and experimental animals can be effectively prevented by inhibitors of arachidonic acid metabolism. Inhibitors of lipoxygenases (LOX) in particular have strong chemopreventive activity in the murine multistage skin carcinogenesis model. In this model some of the LOX products are known to be required for the inflammatory and angiogenic response to tumor promoters and for tumor growth. Unlike other members of the LOX """"""""family,"""""""" 8-LOX is highly inducible in promotion-sensitive mice but not in promotion-resistant mice. It is also constitutively overexpressed in skin tumors. The function of the products of 8-LOX, primarily 8-hydroxyeicosatetraenoic acid (8-HETE), are unknown; however, preliminary data indicate that 8-HETE is an activator of peroxisome proliferator activated receptors (PPARs) in keratinocytes and that PPARs mediate 8-HETE induction of keratin- 1. The applicant has generated an 8- LOX transgenic mouse with the transgene targeted to the epidermis. These mice show a greatly increased propensity for progression from papillomas to carcinomas. Based on these observations, she hypothesizes that one or more of the products of 8-LOX are required for, or contribute to, susceptibility to skin tumor development and that this occurs via a peroxisome proliferator activated receptor (PPAR) mechanism. She also proposes that elevated 8-LOX contributes to tumor development by causing a regenerative response in the epidermis that results in increased stem cell turnover. The specific questions to be addressed are: (1) Does 8-LOX confer increased susceptibility to skin tumor development? (2) How do the products of 8- LOX increase susceptibility? (3) What is the mechanistic basis for the constitutive upregulation of 8-LOX expression in tumors? (4) Do 8-HETE or 9-HODE exert their effects by binding to and activating one or more of the PPAR isoforms in keratinocytes? Is the PPAR alpha isoform required for 8-HETE effects on differentiation and skin tumor susceptibility?
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