Prevention of UVB-induced skin cancer using sulforaphane: roles of AP-1 and Nrf2.

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Non-melanoma skin cancer (NMSC) rates are rising due to factors such as increased UVB light penetrating our atmosphere. Skin cancer, the majority of which is NMSC, accounts for nearly 40% of all diagnosed cancers in the U.S. It is my goal as a scientist to find new, applicable and affordable topical compounds which will be used to reduce the incidence of NMSC in humans. A K07 Career Development Award (CDA) is the most effective means for me to begin to accomplish these objectives and become a productive top-level cancer biologist. To accomplish this goal, I must become well-trained in cancer biology and clinical trial methodology. As part of my career development plan, I have assembled a team of outstanding mentors in skin cancer research, mouse studies, drug formulation, and clinical trials. I will have regular interactions with my mentors and will receive didactic training in subjects such as clinical trial management, bioethics, and biostatistics. I will attend AACR conferences, meetings for the Skin Cancer Program Project Grant and seminars in Cancer Prevention and Control. The Arizona Cancer Center and the Skin Cancer Institute provide me with unique and valuable tools for furthering my training and accomplishing my goals. Scientifically, this CDA will help me to examine the roles of AP-1 and Nrf2 in the mechanism of action of the chemopreventive compound sulforaphane (SF) in UVB-treated skin. SF is an isothiocyanate found in cruciferous vegetables, and inhibits carcinogenesis in several models, possibly due to .induction of the transcription factor Nf E2-related factor 2 (Nrf2). Additionally, SF blocks the activity and DNA-binding ability of the activator protein-i (AP-1) transcription factor, a key component in UVB-induced.skin carcinogenesis. We hypothesize that SF. inhibits DVB-induced skin carcinogenesis and will reduce the,risk of squarnous cell carcinogenesis in patients with sun-damaged skin through a dual mechanism of action: Nrf2 activation leading to reduced pxidative DNA damage, and AP-1 inhibition through direct redox modulation. To.test this hypothesis we will .1)test whether the inhibitory effect of SF on AP-1 transactivation and skin carcinogenesis is due.to.chemical interactions with the DNA binding domain of cFos and/or cJun; 2):test thejnfluence of SF- induced Nrf2 on-protection against acute UVB-induced mouse skin damage and chronic UVB-induced NMSC; ,3)test the safety and efficacy of topical purified SF in humans (a Phase,l/lla clinical.trial)..,