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Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
Xueping Qu, … , Giorgio Cattoretti, Beth Levine
Xueping Qu, … , Giorgio Cattoretti, Beth Levine
Published December 15, 2003
Citation Information: J Clin Invest. 2003;112(12):1809-1820. https://doi.org/10.1172/JCI20039.
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Article Oncology Article has an altmetric score of 8

Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene

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Abstract

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.

Authors

Xueping Qu, Jie Yu, Govind Bhagat, Norihiko Furuya, Hanina Hibshoosh, Andrea Troxel, Jeffrey Rosen, Eeva-Liisa Eskelinen, Noboru Mizushima, Yoshinori Ohsumi, Giorgio Cattoretti, Beth Levine

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Figure 4

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Beclin 1 heterozygous deletion alters cell-growth control in the mammary...
Beclin 1 heterozygous deletion alters cell-growth control in the mammary gland and in splenic germinal centers. (a–d) H&E sections of normal mammary epithelial duct in a beclin 1+/+ mouse (a) and hyperplastic/neoplastic lesions in the mammary glands of beclin 1+/– 6- to 9-month-old virgin mice (b–d), including mammary intraepithelial neoplasia (b), adenomyoepithelioma (c), and acinar neoplasia (d). (e–j) Representative images of BrdU staining of terminal end buds (TEBs) (e and f) and mammary ducts (h and i) in 5-week-old virgin mice and quantitation of percentage of BrdU-positive cells in TEBs (g) and mammary ducts (j). Results shown represent the mean ± SEM of 15 TEBs (g) or 15 ducts (j) from five mice (aged 5 weeks) per genotype. Significant differences were observed between beclin 1+/– and beclin 1+/+ genotypes for percentages of both BrdU-positive TEB cells (P = 0.025, t test) and BrdU-positive ductal cells (P < 0.0001, t test). The arrow in e indicates the neck region, and the arrow in f indicates the cap cell region. (k–n) Representative images of splenic germinal centers (arrow) labeled by PNA staining (38) 8 days after immunization with sheep rbc’s (k and l), and quantitation of the number (m) and size (n) of germinal centers. Results shown represent the mean ± SEM from spleen sections analyzed from five mice per genotype. Significant differences were observed between beclin 1+/– and beclin 1+/+ genotypes for both number (P = 0.027, t test) and size (P = 0.018, t test) of germinal centers. Scale bars: a–f, h, and i, 100 μm; k and l, 1 mm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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