Regulation of hTERT Expression and Function in Newly Immortalized p53(+) Human Mammary Epithelial Cell Lines

Abstract

Abstract : Telomerase is reactivated in almost all human breast cancers; the immortal potential conferred by telomerase is thought to be crucial for malignant progression. Loss of telomeric protection usually leads to widespread genomic instability. This proposal is to study telomerase reactivation and telomere protection in newly immortalized human mammary epithelial cells (HMEC) that retain wild type p53 function, and to determine if these cells may be especially sensitive to therapies that target telomerase activity and telomere protection. Prior work showed that p53 can suppress most, but not all, telomerase expression in newly immortal p53+ HMEC lines until telomeres become extremely short, when an unknown mechanism (termed conversion) relieves this repression. The cyclin-dependent kinase inhibitor p57 may protect cells with these critically shortened telomeres by inhibiting growth until there is sufficient telomerase reactivation to protect the telomeric ends. Our current aims are: (1) Test whether the low telomerase activity, as well as the elevation of p57 expression seen in newly immortal p53+ HMEC, suppress the genomic instability seen prior to immortalization, and if inhibition of telomerase activity and p57 function might efficiently kill these cells. (2) Determine how p53 regulates telomerase activity in newly immortal HMEC lines.