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A Bcl-x_L Transgene Promotes Malignant Conversion of Chemically Initiated Skin Papillomas¹

Gwen Knapp Center for Lupus and Immunology Research [J. C. P., C. M. R., C. B. T.], Committee on Immunology [J. C. P., C. B. T.], Howard Hughes Medical Institute [J. C. P., C. B. T.], and the Department of Medicine, Section of Hematology and Oncology [C. M. R., C. B. T.], University of Chicago, Chicago, Illinois 60637

The role of apoptosis in the pathogenesis of skin cancer was analyzed in mice bearing a Bcl-x_L transgene expressed under the control of the keratin 14 promoter. No spontaneous tumors developed in the skin of these transgenic mice. Bcl-x_L transgenics also failed to develop skin lesions following treatment with the chemical mutagen 9,10-dimethyl-1,2-benzanthracene, or the tumor promoter O-tetradecanoylphorbol-13-acetate. However, Bcl-x_L transgenics developed a two-fold greater number of benign papillomas than control littermates following treatment with the combination of 9,10-dimethyl-1,2-benzanthracene and O-tetradecanoyl-phorbol-13-acetate. More significantly, Bcl-x_L transgenic mice developed invasive squamous cell carcinoma earlier and more frequently than wild-type controls in response to the chemical agents. These data suggest that Bcl-x_L cannot functionally substitute for a mutagenic initiator or mitogenic promoter in tumorigenesis. In contrast, Bcl-x_L overexpression can dramatically increase the malignant conversion rate of benign tumors, suggesting that inhibition of apoptosis can contribute to tumor progression.

¹ Supported by NIH Research Supplement for Underrepresented Minorities P01AI35294 (to J. C. P.), NIH Grant CA11921-02 (to C. B. T.), and by the American Society of Clinical Oncology Young Investigator Award (to C. M. R.).

² To whom requests for reprints should be addressed, at Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, 924 East 57th Street, Room R413A, Chicago, IL 60637.

Received 1/ 9/98. Accepted 3/18/98.

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