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Cross-talk between PI3K and estrogen in the mouse thyroid predisposes to the development of follicular carcinomas with a higher incidence in females

Oncogene volume 29, pages 5678–5686 (2010)Cite this article

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Abstract

It is well known that thyroid disease is more frequent in women than in men; however, the molecular basis for this gender-based difference is still poorly understood. The activation of phosphoinositide 3-kinase (PI3K), through different mechanisms including loss of the PTEN tumor suppressor, is being increasingly recognized as a major player in the development of thyroid neoplastic lesions. Loss of Pten in the mouse thyroid results in a significant increase in the thyrocyte proliferative index, which is more prominent in the female mice. In this study, we show that 52% of the Pten−/− female mice, but only 12% of the males, develop follicular adenomas by 1 year of age. In addition, 50% of female mutants, but only 35% of males older than 1 year of age develop invasive, and often metastatic, follicular carcinomas. Mutant females have a significantly shorter overall survival compared with male mutants. Hormonal manipulation experiments established a direct role of estrogens in controlling the increased thyrocyte proliferation index in mutant females. Furthermore, while genetic ablation of one Cdkn1b allele accelerated the development of neoplastic lesions, it also abolished the gender differences in survival and reduced the difference in neoplastic lesion development rate, underlining a key role of p27 in mediating estrogen action in the thyroid follicular cells. These data, based on a clinically relevant model of thyroid follicular carcinoma, provide, to the best of our knowledge, for the first time in vivo evidence that circulating estrogens are directly responsible for the increased female susceptibility to thyroid disease, at least on activation of the PI3K pathway, and provide new insights into the gender-based differences characterizing thyroid neoplastic disorders.

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Acknowledgements

We thank the Animal Housing and the Histotechnology and Comparative Pathology Facilities of Albert Einstein College of Medicine. This study was supported by the AECC Core Grant, and by NIH grants to ADC (CA97097 and CA128943) and SR (DK15070 and DK20595).

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Author notes

  1. V G Antico-Arciuch and M Dima: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    V G Antico-Arciuch, M Dima & A Di Cristofano

  2. Department of Medicine, University of Chicago, Chicago, IL, USA

    X-H Liao & S Refetoff

  3. Department of Pediatrics and Committee on Genetics, University of Chicago, Chicago, IL, USA

    S Refetoff

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  1. V G Antico-Arciuch
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  2. M Dima
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  3. X-H Liao
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  4. S Refetoff
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  5. A Di Cristofano
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Correspondence to A Di Cristofano.

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Antico-Arciuch, V., Dima, M., Liao, XH. et al. Cross-talk between PI3K and estrogen in the mouse thyroid predisposes to the development of follicular carcinomas with a higher incidence in females. Oncogene 29, 5678–5686 (2010). https://doi.org/10.1038/onc.2010.308

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