Cancer cells must achieve immortality in order to propagate, and this generally occurs by reactivating telomerase — an enzyme that comprises two subunits, mTert and mTerc, and that prevents replicative senescence and crisis (two responses that occur as telomere reserve is exhausted) by maintaining telomere length. But the telomerase story might not be quite as simple as was first thought; Steven Artandi et al. have recently reported that telomerase activity can promote tumorigenesis independently of telomere length.

Transgenic mice were generated that express the catalytic mTert subunit, and the mRNA was shown to be upregulated — compared with that in wild-type mice — in several tissues, including thymus, lung, kidney, mammary glands, heart, muscle and brain. However, heart, muscle and brain tissues did not have a corresponding increase in telomerase activity — as determined by the telomerase repeat amplification protocol (TRAP) assay. One explanation for this could be the low expression levels of the mTerc subunit that were found in these tissues.

So what are the physiological effects of forced mTert expression, and hence telomerase activity? Mouse embryonic fibroblasts (MEFs) from either wild-type or mTert-expressing mice were used to show that the mean telomere length increased from 50–70 kb when mTert was expressed. But, interestingly, these cells undergo culture-induced senescence — a growth arrest that occurs after several passages, and is thought to be independent of telomere length — at the same time and with the same kinetics as wild-type cells. This provides further support that culture-induced senescence, unlike replicative senescence in human cells, is not related to telomere length.

To determine how enforced telomerase expression affected tumorigenesis, wild-type and mTert transgenic mice, both of which had ample telomeres, were treated with the carcinogen dimethylbenz[a]anthracene (DMBA). The high tumour incidence in wild-type mice was not further increased by the expression of mTert. Crossing mTert-transgenic mice to tumour-prone Cdkn2a −/− mice — which are deleted for the Ink4a and Arf tumour suppressors — to generate mTert transgenic Cdkn2a−/− mice neither increased tumour incidence nor altered the tumour spectrum from the sarcomas and lymphomas that are normally found in Cdkn2a−/− mice.

But could a subtle defect that occurs with mTert expression be masked in these highly cancer-prone mice? When monitored over a long period of time, the mTert-expressing mice were found to develop a significant number of breast carcinomas, as well as the normal spectrum of tumours that the wild-type mice develop when they reach old age. This is consistent with the increased telomerase activity in the breast tissue of the transgenic mice. Histological analysis revealed that 67% of one transgenic mouse strain and 33% of another, which expressed lower levels of mTert, developed mammary intraepithelial neoplasia (MIN) — precursors to breast carcinoma — throughout the mammary gland, compared with none of the wild-type control mice.

Telomerase might therefore have a dual function in cancer cells: to lengthen short telomeres, allowing unlimited proliferation, and to promote tumorigenesis by an unknown, telomere-length-independent mechanism. Why this function seems to be restricted to mammary-gland cells, when telomerase activity is high in other tissues, is still to be determined; as is the pathway by which telomerase exerts this effect. This work can only encourage the development of telomerase inhibitors for cancer therapy.