Deletion of Hint1/PKCI in mice enhances susceptibility to the induction of mammary tumors by 7,12-dimethylbenz[a]anthracene (DMBA). Free

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We previously cloned a novel gene Hint1/PKCI that, like the tumor suppressor gene FHIT, belongs to the histidine triad (HIT) family of proteins. Since the function of this gene is not known, we developed Hint1/PKCI deleted mice and found that they have increased susceptibility to induction of gastric tumors by the carcinogen NMBA (Su et. al, Proc Natl Acad Sci U S A, 100: 7824-7829, 2003). To determine if Hint1/PKCI also influences susceptibility to the development of mammary tumors, in the present study we employed a well-established mouse model of DMBA-induced mammary carcinogenesis. Hint1/PKCI +/+, +/–and –/–female mice (8 weeks old) were given 5 intragastric doses of DMBA (dissolved in corn oil) over the course of 5 weeks, at 1 mg/dose per mouse. Equal numbers of the same three groups of mice were given the same volume of corn oil as a control. The occurrence and size of mammary tumors were observed by weekly palpation and recorded. At 140 days after the final dose of DMBA the incidence of mammary tumors in the +/+, +/–and –/–mice was 5.3%, 27.0% and 28.0%, respectively. All of the mice were then sacrificed and complete autopsies performed to determine total tumor incidence. There was a marked and statistically significant (p<0.05) increase in the incidence of mammary tumors in the Hint1/PKCI –/–and +/–mice versus the +/+ mice, since the respective values were 37.8%, 32.0% and 5.3%. We also found a significant increase in ovarian tumors in the –/–and +/–mice when compared to the +/+ mice. The three groups of control mice that received treatment with only corn oil revealed no gross tumors. The histology of the mammary and ovarian tumors and the expression of specific signaling and cell cycle control proteins are being studied. These findings, taken together with our previous study with NMBA, suggest that Hint1/PKCI is a novel tumor suppressor gene. Our findings with the +/–mice also suggest that it is haplo-insufficient. Studies are in progress to elucidate the precise function of this gene.