Telomerase deficiency and telomere dysfunction inhibit mammary tumors induced by polyomavirus middle T oncogene.

Mice transgenic for MUC1 (mucin 1) and polyomavirus middle T (PyMT) develop mammary carcinomas within 15 weeks with 100% penetrance. PyMT-induced mammary tumorigenesis is closely correlated with robust telomerase expression and activity. To assess the role of telomerase activation and telomere maintenance in mammary carcinoma tumorigenesis, we generated mice expressing MUC1 and PyMT (MMT mice) but deficient in the telomerase RNA component, mTerc, on the C57BL/6 background. Successive generational intercrosses of mTerc(-/-)MMT mice produced cohorts with progressively shorter telomeres that were audited for mammary tumor formation. Relative to MMT (N=14) and G0 mTerc(+/-) female controls (G0=14), mTerc(-/-)MMT females (G1=11, G2=15, G3=15 and G4=5) showed decreased tumor volumes and increased tumor latency-MMT=95.6 days; G0 mTerc(+/-)MMT=98.6 days versus G1, G2, G3 and G4 mTerc(-/-)MMT mice with latencies of 122.6, 138.9, 140.7 and 220.9 days, respectively (controls versus G1-G4, P<0.005). The progressive impairment of lung metastasis was also observed with each successive mTerc(-/-)MMT generation. The impairment of tumorigenesis was associated with decreased proliferation of mammary epithelial and tumor cells and increased apoptosis of tumor cells. Together, these results indicate that, in the setting of viral oncoprotein mammary tumorigenesis, telomerase-dependent telomere maintenance facilitates the formation and metastatic progression of mammary tumors.