The study investigates the tumor-suppressive function of the murine gene p27Kip1, which is a candidate human tumor suppressor protein. p27Kip1 is known to inhibit cyclin-dependent kinases and block cell proliferation, and low levels of the p27 protein are often associated with aggressive human carcinomas and poor patient outcomes. However, the causal link between p27 and tumor suppression has been challenging to establish due to the rarity of homozygous inactivating mutations in human tumors. The researchers found that both p27 nullizygous and p27 heterozygous mice are predisposed to tumors in multiple tissues when challenged with γ-irradiation or the chemical carcinogen N-ethyl-N-nitrosourea (ENU). Molecular analyses of tumors in p27 heterozygous mice revealed that the remaining wild-type allele was neither mutated nor silenced, indicating that p27 is haplo-insufficient for tumor suppression. This means that a single functional copy of the gene is sufficient to prevent tumor formation, contrary to the traditional assumption that tumor-suppressor genes require two functional copies to be effective. The study also highlights that p27 haplo-insufficiency may be a common event in sporadic human tumors, as decreased p27 protein expression is observed in various cancers. The authors suggest that restoring p27 expression could be a potential therapeutic strategy for cancer treatment, especially for haplo-insufficient tumor suppressors like p27Kip1.The study investigates the tumor-suppressive function of the murine gene p27Kip1, which is a candidate human tumor suppressor protein. p27Kip1 is known to inhibit cyclin-dependent kinases and block cell proliferation, and low levels of the p27 protein are often associated with aggressive human carcinomas and poor patient outcomes. However, the causal link between p27 and tumor suppression has been challenging to establish due to the rarity of homozygous inactivating mutations in human tumors. The researchers found that both p27 nullizygous and p27 heterozygous mice are predisposed to tumors in multiple tissues when challenged with γ-irradiation or the chemical carcinogen N-ethyl-N-nitrosourea (ENU). Molecular analyses of tumors in p27 heterozygous mice revealed that the remaining wild-type allele was neither mutated nor silenced, indicating that p27 is haplo-insufficient for tumor suppression. This means that a single functional copy of the gene is sufficient to prevent tumor formation, contrary to the traditional assumption that tumor-suppressor genes require two functional copies to be effective. The study also highlights that p27 haplo-insufficiency may be a common event in sporadic human tumors, as decreased p27 protein expression is observed in various cancers. The authors suggest that restoring p27 expression could be a potential therapeutic strategy for cancer treatment, especially for haplo-insufficient tumor suppressors like p27Kip1.