Telomerase: a breast cancer chemopreventive and therapeutic target

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Telomeres are repetitive DNA sequences at the end of linear chromosomes. Each time a cell divides some telomeric sequences are lost. When telomeres are short, cells enter an irreversible growth arrest state called replicative senescence. In most instances cells become senescent before they can become a cancer cell. However, almost all cancer cells are immortal, having overcome cellular senescence. Maintenance of telomere stability is required for cells to escape from replicative senescence and proliferate indefinitely. Telomerase, a cellular reverse transcriptase, is upregulated or reactivated in most cancers and helps to stabilize telomere length by adding TTAGGG repeats onto the telomeres. The correlation between telomerase activity and human tumors suggests that tumor growth requires reactivation of telomerase and that telomerase inhibitors represent a novel class of chemotherapeutic agents. Human cancer cells treated with oligonucleotide-based antisense chemistries (peptide nucleic acid or 2'-O-meRNA), directed against the template region of telomerase RNA, inhibit telomerase activity inside cells at pharmacological dosages. Telomerase inhibition leads to progressive telomere shortening, causing immortal human breast epithelial cells to undergo apoptosis. Telomerase is also being considered as a target for molecular chemopreventive strategies to inhibit immortalization. Expressing a dominant-negative mutant of the telomerase catalytic subunit prevents the spontaneous immortalization of TP53-heterozygous Li-Fraumeni Syndrome-derived breast epithelial cells. These results not only validate telomerase as a target for breast cancer prevention and therapy, but also supply insights into the properties that successful anti-telomerase agents will require. To confirm action through a telomerase-dependent mechanism, inhibitors but not chemically-related molecules should (i) reduce telomerase activity but not initially affect cell growth rates; (ii) lead to progressive shortening of telomeres with each cell division; and (iii) cause cells to die or undergo growth arrest in a time frame dependent on initial telomere length.