Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.
Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. Among the many factors that may contribute to this species variance are differences in telomere length and regulation. Telomeres comprise the nucleoprotein complexes that cap the ends of eukaryotic chromosomes and are maintained by the reverse transcriptase, telomerase. In human cells, insufficient levels of telomerase lead to telomere attrition with cell division in culture and possibly with ageing and tumorigenesis in vivo. In contrast, critical reduction in telomere length is not observed in the mouse owing to promiscuous telomerase expression and long telomeres. Here we provide evidence that telomere attrition in ageing telomerase-deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion-bridge breakage that leads to the formation of complex non-reciprocal translocations--a classical cytogenetic feature of human carcinomas. Our data suggest a model in which telomere dysfunction brought about by continual epithelial renewal during life generates the massive ploidy changes associated with the development of epithelial cancers.
Artandi
S E
SE
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Chang
S
S
Lee
S L
SL
Alson
S
S
Gottlieb
G J
GJ
Chin
L
L
DePinho
R A
RA
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics; D000375:Aging / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016158:Genes, p53; D006801:Humans; D007621:Karyotyping; D008223:Lymphoma / Q000201:enzymology / Q000235:genetics; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics; D051379:Mice; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012513:Sarcoma, Experimental / Q000201:enzymology / Q000235:genetics; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016615:Telomere; D014178:Translocation, Genetic
D019098:Telomerase