We have derived and mated separate strains of transgenie mice that carry either the v-Ha-ras or the c-myc gene driven by the mouse mammary tumor virus (MMTV) promoter/enhancer. Mice carrying the MMTW v-Ha-ras transgene manifest two distinct disturbances of cell growth. The first, a benign hyperpiasia of the Harderian lacrimal gland, is diffuse, involves the entire gland, and likely requires only the abnormal action of the v-Ha-ras gene. The second involves the focal development of malignancies of mammary, salivary, and lymphoid tissue and likely requires additional somatic events. When the MMTVlv-Ha-ras and MMTWc-myc strains ate crossed to yield hybrid mice, their joint action results in a dramatic and synergistic acceleration of tumor formation. Since these tumors arise stochastically and are apparently monoclonai in origin, additional somatic events appear necessary for their full malignant progression, even in the presence of activated v-Ha-ras and c-myc transgenes. introduction

Oncogenesis is a multistep process that is likely to involve the successive activation of several oncogenes. This notion is strongly supported by experiments involving the use of cultured cells, particularly those in which primary cells are transformed by the complementary action of two oncogenes (Land et al., 1983; Newbold and Overwell, 1983; Ruley, 1983; Eliyahu et al., 1984; Jenkins et al., 1984; Parada et al., 1984; Lee et al., 1985; Yancopoulos et al., 1985; Graf et al., 1988; Schwartz et al., 1988). Although such experiments have provided powerful systems for evaluating the action of known oncogenes and for identifying new ones (Der et al., 1982; Parada et al., 1982; Santos et al., 1982) they do not view malignant transformation in the context in which it actually occurs, namely, the living organism. For example, tissue culture experiments cannot easily assess the influence of blood supply,