Pituitary tumorigenesis in Men1+/− mice depends on Cdk4
Previous studies demonstrated that Men1+/− mice develop tumors in the anterior pituitary with a latency of 9-13 months 3, 4. Cdk4−/− mice exhibit hypoplasia of the anterior pituitary and pancreatic islets during postnatal periods, while embryonic development of these endocrine tissues occurs normally 21-23. To determine whether CDK4 activity is required for tumorigenesis initiated by the loss of menin, Men1+/−; Cdk4−/− mice were generated by crossbreeding and characterized in comparison with Men1+/−; Cdk4+/+ (Cdk wild-type) littermates. Mice were euthanized at 15 months of age for pathological examinations. None of 12 wild-type (Men1+/+) mice generated from the breeding displayed pituitary tumors, while 45% of Men1+/− mice (n=31) showed pituitary tumors (Fig. 1A, B). It is noteworthy that no Men1+/− males exhibited macroscopic pituitary tumors at 15 months of age (n=11), whereas 14 (70%) of 20 Men1+/− female mice had developed pituitary tumors. This gender-specific effect on pituitary tumorigenesis is consistent with a previous study, which showed 79% of Men1+/− mice that developed pituitary tumors were females 4. Strikingly, none of 30 Men1+/−; Cdk4−/− mice (11 males and 19 females) displayed pituitary tumors. These observations indicate that pituitary tumorigenesis induced by menin deficiency depends on CDK4 activity. Furthermore, the pituitaries from the entire cohort of Men1+/−; Cdk4−/− mice remained hypoplastic, in a manner similar to the single Cdk4−/− mice throughout their 15-month lifespan (Fig. 1A). Our previous study demonstrated that CDK4 is an essential driving force for estrogen- or GHRH-induced proliferation in murine pituicytes 23. Thus, these data indicate that CDK4 is required for both physiological and tumorigenic control of cell cycle progression in this particular endocrine tissue.
To determine whether the requirement for CDK4 in menin-associated tumorigenesis is unique among the G1-regulatory CDKs or there is functional overlap, we next examined the impact of Cdk2-deficiency on tumorigenesis of Men1+/− mice, by generating Men1+/−; Cdk2−/− and Men1+/−; Cdk2+/+ (Cdk wild-type) littermates. In sharp contrast to Men1+/−; Cdk4−/− mice, 51% of examined Men1+/−; Cdk2−/− mice (n=29) showed macroscopic pituitary tumors comparable to those in Men1+/−; Cdk wild-type mice (Fig. 1A, 1B). Interestingly, we observed tumors in 4 (24%) of 17 Men1+/−; Cdk2−/− male mice and 11 (92%) of 12 Men1+/−; Cdk2−/− female mice. This may imply that Cdk2 deficiency modestly promoted pituitary tumorigenesis under the conditions of the study, although examinations of a larger cohort will be necessary to be conclusive. Regardless, these data indicate that the absence of CDK2 can be compensated, and has no impact on restraining the process of pituitary tumorigenesis induced by menin deficiency.