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Pten is essential for embryonic development and tumour suppression

Abstract

The PTEN gene encodes a dual-specificity phosphatase mutated in a variety of human cancers. PTEN germline mutations are found in three related human autosomal dominant disorders, Cowden disease (CD), Lhermitte-Duclos disease (LDD) and Bannayan-Zonana syndrome (BZS), characterized by tumour susceptibility and developmental defects. To examine the role of PTEN in ontogenesis and tumour suppression, we disrupted mouse Pten by homologous recombination. Pten inactivation resulted in early embryonic lethality. Pten–/– ES cells formed aberrant embryoid bodies and displayed an altered ability to differentiate into endodermal, ectodermal and mesodermal derivatives. Pten+/– mice and chimaeric mice derived from Pten+/– ES cells showed hyperplastic-dysplastic changes in the prostate, skin and colon, which are characteristic of CD, LDD and BZS. They also spontaneously developed germ cell, gonadostromal, thyroid and colon tumours. In addition, Pten inactivation enhanced the ability of ES cells to generate tumours in nude and syngeneic mice, due to increased anchorage-independent growth and aberrant differentiation. These results support the notion that PTEN haploinsufficiency plays a causal role in CD, LDD and BZS pathogenesis, and demonstrate that Pten is a tumour suppressor essential for embryonic development.

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Figure 1: Targeted disruption of Pten in the mouse germ line.
Figure 2: Histopathological analysis of tissue abnormalities developed in Pten chimaeric and heterozygous mice.
Figure 3: Histopathological analysis of the tumours in Pten chimaeric and heterozygous mice.
Figure 4: Enhanced ability of Pten–/– ES cells to induce teratomas in syngeneic mice.
Figure 5: In vitro differentiation is altered in Pten–/– embryoid bodies (EBs).
Figure 6: Pten–/– ES cells show an enhanced ability to grow in an anchorage-independent manner.

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Acknowledgements

We thank K. Podsypanina, P. Fisher and R. Parsons for useful discussion and for exchanging preliminary and unpublished data; K. Witty and K. Manova for the analysis of EBs features; M. Barna for help with the editing of the manuscript; J. H. Dong and W. Mark for help with the generation and the management of the Pten mutants; and J. Rosai for critical suggestions in the analysis of the pathological features of the mice. P.P.P. is a Scholar of the Leukemia Society of America. This work was supported by the Sloan-Kettering Institute (CA-08748).

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Correspondence to Pier P. Pandolfi.

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Cristofano, A., Pesce, B., Cordon-Cardo, C. et al. Pten is essential for embryonic development and tumour suppression . Nat Genet 19, 348–355 (1998). https://doi.org/10.1038/1235

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