Highly expressed in cancer 1 (HEC1) forms part of a protein complex sited at the kinetochore that ensures the correct interaction with microtubules at metaphase prior to chromatid segregation. Moreover, as its name implies, HEC1 is overexpressed in a variety of transformed cell lines and its expression levels correlate with stage and prognosis in lung cancer. Benezra and colleagues developed inducible Hec1 mouse models in which Hec1 expression was regulated by either the presence (Tet-on) or absence (Tet-off) of doxycycline. Using mouse embryonic fibroblasts derived from the Tet-on mice, the authors established that the transgenic HEC1 was localized at the kinetochore and that its overexpression did not lead to an overt increase in proliferation rates, although a higher number of mouse embryonic fibroblasts expressing HEC1 were delayed in exiting mitosis. Further analyses of these cells showed that they develop aneuploidy after 72 hours in culture in the presence of doxycycline. To measure the effect of HEC1 overexpression on the cell cycle, the authors used lymphocytes from the transgenic mice as these are easier to synchronize. Proteins involved in the mitotic checkpoint, such as MAD2, were highly expressed in these cells and did not show their normal cyclical expression, indicating that the mitotic checkpoint is overactive in cells overexpressing HEC1.
Do these alterations induce tumour formation? After 14–18 months, 12.8% of the mice expressing Hec1 developed lung adenomas compared with 1.4% of control mice, and 25.5% developed liver tumours compared with 11.4% of controls. Importantly, aneuploidy and high expression levels of MAD2 were evident in lung tumours from the transgene-expressing mice but not the control mice.
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