p27 and cyclin E/D2 associations in testicular germ cell tumors: implications for tumorigenesis.

The cyclins are key regulators of cell cycle progression and cellular proliferation. We have previously shown that in testicular germ cell tumors, cyclin E expression correlates with more aggressive tumors, higher clinical stage, and the presence of pulmonary metastases. Here, we have examined the association between cyclin activation and the proliferative rate of the pluripotential testicular tumor cell. We have shown that in a panel of 30 testicular germ cell tumors, 15 cases (50%) expressed the cyclin dependent kinase inhibitor p27; of note, 13 of 14 embryonal carcinomas (93%) coexpressed cyclin E and p27, suggesting inhibition of this cyclin. We show that 25 of 30 (83%) of the testicular germ cell tumors express cyclin D2. Using immunoprecipitation assays from the embryonal carcinoma cell line NTera2 or from tumor cell extracts, we have shown that cyclin D2 is complexed with p27, consistent with its known ability to sequester and block the cyclin E inhibitory function of p27. From these results, we propose a model in testicular germ cell tumors, in particular embryonal carcinomas, whereby the overexpression of cyclin D2, a gene localized on chromosome 12p--a region of DNA amplification in germ cell tumors--leads to the functional sequestration of p27 in the presence of cyclin E and cyclin D2, thus favoring cellular proliferation.