LUNG-TUMORS IN MICE EXPRESSING AN ANTISENSE RAR-BETA-2 TRANSGENE

Retinoic acid has been shown to be an anticancer agent, and a growing literature suggests that it is the nuclear retinoic acid receptor beta 2 (RAR beta 2) that is primarily responsible for mediating this effec t, at least in some systems, To determine whether partial inactivation of RAR beta 2 would predispose to lung cancer in mice, we generated t hree transgenic lines expressing antisense sequences. When killed at 1 3-3/4-18 months of age, 21/36 animals had a total of 43 pulmonary tumo rs superficially visible upon necropsy, whereas among 23 nontransgenic mice, only 1 had a single visible lung tumor, A twofold higher incide nce of lung tumors was seen in homozygous vs, hemizygous antisense mic e, The endogenous RAR beta 2 message level was reduced in transgenic l ung tissue and further reduced in the tumors, RAR beta 4, a truncated isoform derived from the same transcript as RAR beta 2, does not carry the sequence identified by the antisense construct and its message wa s not as strongly affected, Immunofluorescence studies showed that RAR beta was virtually undetectable in the tumors, but present in normal tissue, We conclude that RAR beta 2, but probably not RAR beta 4, play s an important role in suppression of murine lung tumorigenesis.