TELOMERASE ACTIVATION IN MOUSE MAMMARY-TUMORS - LACK OF DETECTABLE TELOMERE SHORTENING AND EVIDENCE FOR REGULATION OF TELOMERASE RNA WITH CELL

Activation of telomerase in human cancers is thought to be necessary t o overcome the progressive loss of telomeric DNA that accompanies prol iferation of normal somatic cells. According to this model, telomerase provides a growth advantage to cells in,which extensive terminal sequ ence loss threatens viability. To test these ideas, we have examined t elomere dynamics and telomerase activation during mammary tumorigenesi s in mice carrying a mouse mammary tumor virus long terminal repeat-dr iven Wnt-1 transgene. We also analyzed Wnt-1-induced mammary tumors in mice lacking p53 function. Normal mammary glands, hyperplastic mammar y glands, and mammary carcinomas all had the long telomeres (20 to 50 kb) typical of Mus musculus and did not show telomere shortening durin g tumor development. Nevertheless, telomerase activity and the RNA com ponent of the enzyme were consistently upregulated in Wnt-1-induced ma mmary tumors compared with normal and hyperplastic tissues. The upregu lation of telomerase activity and RNA also occurred during tumorigenes is in p53-deficient mice. The expression of telomerase RNA correlated strongly with histone H4 mRNA in all normal tissues grad tumors, indic ating that the RNA component of telomerase is regulated,vith cell prol iferation. Telomerase activity in the tumors was elevated to a greater extent than telomerase RNA, implying that the enzymatic activity of t elomerase is regulated at additional levels. Our data suggest that the mechanism of telomerase activation in mouse mammary tumors is not lin ked to global loss of telomere function but involves multiple regulato ry events including upregulation of telomerase RNA in proliferating ce lls.