COOPERATION BETWEEN FOLLICULAR ORNITHINE DECARBOXYLASE AND V-HA-RAS INDUCES SPONTANEOUS PAPILLOMAS AND MALIGNANT CONVERSION IN TRANSGENIC SKIN

Ornithine decarboxylase (ODC) is aberrantly regulated in tumor cells a nd results in high basal levels of ODC and polyamines in many epitheli al tumors. To determine if elevated ODC/polyamine levels can co-operat e with a mutant Ha-ras gene in mouse skin tumorigenesis, double transg enic mice were generated by breeding K6/ODC transgenic mice with TG,AC v-Ha-ras transgenic mice. A K6 keratin promoter drives the ODC transg ene in K6/ODC transgenic mice, which results in elevated ODC/polyamine levels directed to the outer root sheath cells of hair follicles, TG, AC transgenic mice carry a v-aa-ras transgene while still retaining tw o normal c-aa-ras alleles, Transgenic mice that possess only the K6/OD C or the v-Ha-ras transgene did not develop tumors unless treated with either a carcinogen or a tumor promoter, respectively. However, a hig h percentage of double transgenic mice possessing both the K6/ODC and v-Ha-ras transgenes developed spontaneous tumors. All tumors were well -differentiated keratoacanthomas, some of which progressed to carcinom as within 2 months. The development and the maintenance of these ODC/r as tumors was ODC-dependent since a-difluoromethylornithine (DFMO), a specific ODC inhibitor, prevented the formation and caused the regress ion of these tumors. These findings indicate that ODC overexpression a nd an activated Ha-ras are sufficient to produce a high rate of malign ant transformation in an animal model. The ODC/ras double transgenic m ouse provides a simple in vivo model without the use of chemical carci nogens or tumor promoters in which to test downstream effecters that p lay a key role in mediating the development of epithelial tumors resul ting from the co-operation between ODC and v-Ha-ras.