INT-6, A HIGHLY CONSERVED, WIDELY EXPRESSED GENE, IS MUTATED BY MOUSEMAMMARY-TUMOR VIRUS IN MAMMARY PRENEOPLASIA

With a unique mouse mammary tumor model system in which mouse mammary tumor virus (MMTV) insertional mutations can be detected during progre ssion from preneoplasia to frank malignancy, including metastasis, we have discovered a new common integration site (designated Int-6) for M MTV in mouse mammary tumors, MMTV was integrated into Int-6 in a mamma ry hyperplastic outgrowth line, its tumors and metastases, and two ind ependent mammary tumors arising in unrelated mice, The Int-6 gene is u biquitously expressed as a 1.4-kb RNA species in adult tissues and is detected beginning at day 8 of embryonic development, The nucleotide s equence of Int-6 is unrelated to any of the known genes in the GenBank database. MMTV integrates within introns of the gene in the opposite transcriptional orientation, In each tumor tested, this results in the expression of a truncated Int-6/long terminal repeat (LTR) chimeric R NA species which is terminated at a cryptic termination signal in the MMTV LTR Since the nonrearranged Int-6 alleles in these tumors contain no mutations, we favor the conclusion that truncation of the Int-6 ge ne product either biologically activates its function or represents a dominant-negative mutation.