[HTML][HTML] Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene

X Qu, J Yu, G Bhagat, N Furuya… - The Journal of …, 2003 - Am Soc Clin Investig
X Qu, J Yu, G Bhagat, N Furuya, H Hibshoosh, A Troxel, J Rosen, EL Eskelinen…
The Journal of clinical investigation, 2003Am Soc Clin Investig
Malignant cells often display defects in autophagy, an evolutionarily conserved pathway for
degrading long-lived proteins and cytoplasmic organelles. However, as yet, there is no
genetic evidence for a role of autophagy genes in tumor suppression. The beclin 1
autophagy gene is monoallelically deleted in 40–75% of cases of human sporadic breast,
ovarian, and prostate cancer. Therefore, we used a targeted mutant mouse model to test the
hypothesis that monoallelic deletion of beclin 1 promotes tumorigenesis. Here we show that …
Malignant cells often display defects in autophagy, an evolutionarily conserved pathway for degrading long-lived proteins and cytoplasmic organelles. However, as yet, there is no genetic evidence for a role of autophagy genes in tumor suppression. The beclin 1 autophagy gene is monoallelically deleted in 40–75% of cases of human sporadic breast, ovarian, and prostate cancer. Therefore, we used a targeted mutant mouse model to test the hypothesis that monoallelic deletion of beclin 1 promotes tumorigenesis. Here we show that heterozygous disruption of beclin 1 increases the frequency of spontaneous malignancies and accelerates the development of hepatitis B virus–induced premalignant lesions. Molecular analyses of tumors in beclin 1 heterozygous mice show that the remaining wild-type allele is neither mutated nor silenced. Furthermore, beclin 1 heterozygous disruption results in increased cellular proliferation and reduced autophagy in vivo. These findings demonstrate that beclin 1 is a haplo-insufficient tumor-suppressor gene and provide genetic evidence that autophagy is a novel mechanism of cell-growth control and tumor suppression. Thus, mutation of beclin 1 or other autophagy genes may contribute to the pathogenesis of human cancers.
The Journal of Clinical Investigation