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Immortalization of Primary Human Prostate Epithelial Cells by c-Myc

¹ Molecular Oncology Laboratory, Cancer Research UK, London Research Institute; ² Center for Cutaneous Biology, Institute for Cell and Molecular Sciences, London, United Kingdom; ³ University of Cambridge, Cancer Research UK, Department of Oncology and the Medical Research Council Cancer Cell Unit, Hutchinson/Medical Research Council Research Centre, Cambridge, United Kingdom; ⁴ Department of Pathology, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain; ⁵ Free University of Brussels, Laboratory of Molecular Virology, Faculty of Medicine, Brussels, Belgium; and ⁶ Cytogenetics Unit, Biotechnology Program and ⁷ Experimental Therapeutics Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Requests for reprints: Jesús Gil, Molecular Oncology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44-2072693594; Fax: 44-2072693094; E-mail: jesus.gil{at}cancer.org.uk.

A significant percentage of prostate tumors have amplifications of the c-Myc gene, but the precise role of c-Myc in prostate cancer is not fully understood. Immortalization of human epithelial cells involves both inactivation of the Rb/p16^INK4a pathway and telomere maintenance, and it has been recapitulated in culture by expression of the catalytic subunit of telomerase, hTERT, in combination with viral oncoproteins. Here, we show the immortalization of human prostate epithelial cells (HPrEC) by a single genetic event, the expression of the c-Myc oncogene. Myc stabilizes telomere length in HPrEC through up-regulation of hTERT expression and overrides the accumulation of cell cycle inhibitory proteins, such as p16^INK4a. Overall, HPrECs expressing c-Myc retain many characteristics of normal cells, such as the induction of a senescence-like growth arrest in response to oncogenic Ras, an intact p53 response, and an absence of gross karyotypic abnormalities. However, HPrECs expressing c-Myc lack a Rb/p16^INK4a checkpoint and can be transformed without the need for additional genetic lesions in that pathway. These results give a partial explanation for the physiologic role of c-Myc overexpression in prostate cancer.

Key Words: senescence • telomerase • prostate • transformation • Ras

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