TELOMERASE ACTIVITY IS ASSOCIATED WITH CELL-CYCLE DEREGULATION IN HUMAN BREAST-CANCER

Deregulation of the cell cycle by abnormal expression of one or severa l cell cycle regulatory proteins is a common finding in malignant tumo rs and might be a prerequisite for cancer development. Telomerase acti vity is an immortalization marker that is found in most cancers and fo r which an association with an active cell cycle has been implicated. In the tissue of 106 human breast carcinomas, we analyzed the relation ship between telomerase activity levels and defects in the cell cycle machinery with a focus on the retinoblastoma protein (pRE) pathway(s). The fraction of telomerase-positive tumors was 85%, and large differe nces in telomerase activity were found. Overexpression of cyclin D1 an d/or cyclin E, in combination with a normal pRB, was a typical feature of tumors with high telomerase activity levels. Down-regulation of p1 6(INK4) was not related per se to telomerase activity, but tumors with low p16(INK4) in combination with cyclin D1 or E overexpression demon strated high activity. Tumor cell proliferation, determined by Ki-67 e xpression, correlated significantly to telomerase activity levels. The re was, however, not a strict association between proliferation rate a nd telomerase activity, because tumors with inactivated pRB had the hi ghest Ki-67 fractions but intermediate telomerase activity. Also, cycl in D1 overexpression was associated with high telomerase levels withou t an increase in tumor cell proliferation. The present study indicates that telomerase activation occurs preferentially in breast cancers wi th certain cell cycle regulatory defects and that telomerase activity levels may depend on the specific defect(s).