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Targeted Disruption of Stat3 Reveals a Major Role for Follicular Stem Cells in Skin Tumor Initiation

¹ Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas and ² Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: John DiGiovanni, Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, 1808 Park Road 1C, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9414; Fax: 512-237-2522; E-mail: jdigiova{at}mdanderson.org.

Key Words: Stat3 • keratinocytes • stem cells • tumor initiation • skin carcinogenesis

The initiation stage of mouse skin carcinogenesis involves the induction of mutations in keratinocyte stem cells (KSC), which confers a selective growth advantage allowing clonal expansion during tumor promotion. Targeted disruption of signal transducer and activator of transcription 3 (Stat3) in bulge region KSCs was achieved by treating K15.CrePR1 x Stat3^fl/fl mice with RU486. Deletion of Stat3 prior to skin tumor initiation with 7,12-dimethylbenz(a)anthracene significantly increased the number of apoptotic KSCs and decreased the frequency of Ha-ras codon 61 A¹⁸²T transversion mutations in this cell population compared with wild-type littermates. Targeted disruption of Stat3 in bulge region KSCs at the time of initiation also dramatically reduced the number of skin tumors (by 80%) produced following promotion with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. These results show that Stat3 is required for the survival of bulge region KSCs during tumor initiation. Furthermore, these data provide direct evidence that bulge region KSCs are the primary targets for the initiation of skin tumors in this model system. [Cancer Res 2009;69(19):7587–94]