Lung tumors in mice expressing an antisense RARbeta2 transgene.

Retinoic acid has been shown to be an anticancer agent, and a growing literature suggests that it is the nuclear retinoic acid receptor beta2 (RARbeta2) that is primarily responsible for mediating this effect, at least in some systems. To determine whether partial inactivation of RARbeta2 would predispose to lung cancer in mice, we generated three transgenic lines expressing antisense sequences. When killed at 13-3/4-18 months of age, 21/36 animals had a total of 43 pulmonary tumors superficially visible upon necropsy, whereas among 23 nontransgenic mice, only 1 had a single visible lung tumor. A twofold higher incidence of lung tumors was seen in homozygous vs. hemizygous antisense mice. The endogenous RARbeta2 message level was reduced in transgenic lung tissue and further reduced in the tumors. RARbeta4, a truncated isoform derived from the same transcript as RARbeta2, does not carry the sequence identified by the antisense construct and its message was not as strongly affected. Immunofluorescence studies showed that RARbeta was virtually undetectable in the tumors, but present in normal tissue. We conclude that RARbeta2, but probably not RARbeta4, plays an important role in suppression of murine lung tumorigenesis.