National Cancer Research Institute South of England
Prostate Cancer Collaborative
Research

Identification and isolation of novel telomerase suppressor genes involved in sporadic prostate cancer

Author
Prof Robert Newbold
Brunel University

Prostate cancer is the most commonly diagnosed malignant neoplasm and the second leading cause of deaths in males in the west, and its incidence is increasing at an alarming rate. It has been predicted that prostate cancer will be the most common cause of death in males by 2010. There is no curative therapy once the carcinoma has spread locally or distantly. There has been an increase in the early detection of prostate cancer but current methodologies do not distinguish between cancers that will remain indolent, and require no treatment, and those that will prove to be highly progressive and life threatening. Therefore there is an urgent need for molecular markers to detect the malignant nature and pathological states of the human prostate and to develop new approaches to treat patients with progressive prostate cancer.
Our aim is to identify and characterise new prostate cancer-specific gene(s) that could provide new potential markers for diagnosis, prognosis and aid in the development of new targeted treatment.

Telomerase may be used for targeted therapy for prostate cancer because high telomerase activity has been detected in 90% of prostate tumors whereas normal and BPH tissues have very low or absent activity.

Telomerase is a specialised RNA dependent ribonucleoprotein polymerase that maintains and elongates telomeres by telomeric repeat sequence TTAGGG at the ends of chromosomes. Telomerase activation is required for cells to overcome replicative senescence and to obtain immortal capacity, and is therefore a critical step in carcinogenesis.

We are using a technique called microcell-mediated monochromosome transfer for genetic analysis. The method allows a single normal human chromosome, tagged with a hygromycin resistance gene, to be introduced into a well established prostate cell line PC-3 and maintained therein by selection as an intact functional and structural entity. By using this technique, individual chromosomes can be screened for the presence of active genes specifying a particular cellular phenotype on the basis of genetic complementation.

To date, we have been able to transfer all 22 normal human chromosomes plus the X chromosome individually into PC-3. We have assayed telomerase activity in 10 sets of monochromosomal hybrids of PC-3, using the commercially available telomere repeat amplification protocol (TRAP) kit. Initial results with PC-3/Chr10 and PC-3/Chr17 hybrids revealed a high percentage of hybrids exhibiting telomerase repression, suggesting that telomerase repressor sequences exist on these chromosomes.

A typical example of a TRAP assay of PC-3/Chr 4
clones showing telomerase activity

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Molecular Pathology

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Development of Normal Prostate
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Subtractive Hybridization
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Tumor micro-environment in early prostate cancer

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Contact us on Email: cbell@icr.ac.uk Tel: 0208 643 8901 Fax: 0208 770 7290 This page last modified: 6/11/02