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PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer

Oncogene volume 28, pages 509–517 (2009)Cite this article

Abstract

Inactivation and silencing of PTEN have been observed in multiple cancers, including follicular thyroid carcinoma. PTEN (phosphatase and tensin homologue deleted from chromosome 10) functions as a tumour suppressor by opposing the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Despite correlative data, how deregulated PTEN signalling leads to thyroid carcinogenesis is not known. Mice harbouring a dominant-negative mutant thyroid hormone receptor β (TRβPV/PV mice) spontaneously develop follicular thyroid carcinoma and distant metastases similar to human cancer. To elucidate the role of PTEN in thyroid carcinogenesis, we generated TRβPV/PV mice haploinsufficient for Pten (TRβPV/PVPten+/− mouse). PTEN deficiency accelerated the progression of thyroid tumour and increased the occurrence of metastasis spread to the lung in TRβPV/PVPten+/− mice, thereby significantly reducing their survival as compared with TRβPV/PVPten+/+ mice. AKT activation was further increased by two-fold in TRβPV/PVPten+/− mice thyroids, leading to increased activity of the downstream mammalian target of rapamycin (mTOR)–p70S6K signalling and decreased activity of the forkhead family member FOXO3a. Consistently, cyclin D1 expression was increased. Apoptosis was decreased as indicated by increased expression of nuclear factor-κB (NF-κB) and decreased caspase-3 activity in the thyroids of TRβPV/PVPten+/− mice. Our results indicate that PTEN deficiency resulted in increased cell proliferation and survival in the thyroids of TRβPV/PVPten+/− mice. Altogether, our study provides direct evidence to indicate that in vivo, PTEN is a critical regulator in the follicular thyroid cancer progression and invasiveness.

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Abbreviations

AKT:

protein kinase B

mTOR:

mammalian target of rapamycin

PI3K:

phosphatidylinositol 3-kinase

TRβ:

thyroid hormone receptor β gene

TSH:

thyroid-stimulating hormone

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Acknowledgements

We thank Dr Hao Ying for assistance in the determination of thyroid function tests. This research was supported by the Intramural Research Program of Center for Cancer Research, National Cancer Institute, National Institutes of Health.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    C J Guigon, L Zhao & S-Y Cheng

  2. Department of Pathology, Wake Forest University, Winston-Salem, NC, USA

    M C Willingham

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  1. C J Guigon
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  2. L Zhao
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  3. M C Willingham
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  4. S-Y Cheng
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Correspondence to S-Y Cheng.

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Guigon, C., Zhao, L., Willingham, M. et al. PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer. Oncogene 28, 509–517 (2009). https://doi.org/10.1038/onc.2008.407

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