SUSCEPTIBILITY TO TUMORS INDUCED IN MICE BY ETHYLNITROSOUREA IS INDEPENDENT OF RETINOBLASTOMA GENE DOSAGE

The retinoblastoma gene (RB) is a classical tumor suppressor. Several studies have shown that RB dosage is important in determining biologic al effects. To explore the effect of RB dosage on susceptibility to ca ncer, three groups of congenic C57BL/6 mice, each of which expresses a different amount of Rb protein from one, two, or three alleles, were treated at postnatal day 12 with a single 60-mg/kg body weight i.p. do se of the DNA-alkylating agent N-ethyl-N'-nitrosourea (ENU). Mice hete rozygous for the RB gene developed characteristic pituitary tumors wit h nearly complete penetrance, whether or not they were treated with EN U. Tumors initiated earlier or progressed more rapidly, however, in EN U-treated mice. Furthermore, although mice treated with ENU had a high er incidence of several nonpituitary tumors compared with untreated co ntrols, no significant differences in the incidence of these tumors we re found between wild-type mice (mRB(+/+)), mice carrying only one nor mal RB allele and deficient in Rb protein expression (mRB(+/-)), and m ice overexpressing Rb protein from two normal murine RB alleles and a human RB transgene (mRB(+/+) hRB(+/-)). These studies underscore the t issue and mechanistic specificity of tumor predisposition caused by an inherited 50% reduction in RB dosage and indicate that most ENU-induc ed tumors occur independent of RB inactivation. Nonetheless, they sugg est that certain point mutations induced by ENU may participate in the sequence of molecular steps involved in progression of tumor-prone, R B-deficient cells to the fully malignant state.