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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.

Antico-Arciuch VG, Dima M, Liao XH, Refetoff S, Di Cristofano A - Oncogene (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

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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Analysis of the expression levels of several thyroid differentiation and functional markers in thyroids from male (m) and female (f) control and young mutant mice, as well as adenoma-and carcinoma-bearing female mutants.
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Figure 3: Analysis of the expression levels of several thyroid differentiation and functional markers in thyroids from male (m) and female (f) control and young mutant mice, as well as adenoma-and carcinoma-bearing female mutants.

Mentions: In order to characterize the effects of PI3K constitutive activation on the genes responsible for thyroid specification and function, we determined by quantitative real time PCR the expression levels of a battery of thyroid-relevant genes (Figure 3). Loss of Pten, as well as neoplastic transformation of Pten−/− thyrocytes, did not significantly or consistently change the expression of the three master genes involved in the specification and differentiation of the thyroid gland, namely Foxe1, Nkx2-1, and Pax8. Hyperplastic Pten−/− thyroids had normal mRNA levels of Tshr, Duox2, Slc5a5 (NIS), and slightly reduced expression of Tpo, Tg, and Duox1. Interestingly, we found that the expression of Tpo, Duox1, and Slc5a5 was significantly higher in thyroids from female mice, irrespective of Pten status, suggesting a role for estrogen in the control of the expression of these genes. Carcinomas and, to a lesser extent, adenomas developing in Pten−/− mice showed an increase in the expression of Tshr, as well as a reduction of mRNA levels for Duox1, Duox2 and, notably, Slc5a5.


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

Antico-Arciuch VG, Dima M, Liao XH, Refetoff S, Di Cristofano A - Oncogene (2010)

Analysis of the expression levels of several thyroid differentiation and functional markers in thyroids from male (m) and female (f) control and young mutant mice, as well as adenoma-and carcinoma-bearing female mutants.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967724&req=5

Figure 3: Analysis of the expression levels of several thyroid differentiation and functional markers in thyroids from male (m) and female (f) control and young mutant mice, as well as adenoma-and carcinoma-bearing female mutants.
Mentions: In order to characterize the effects of PI3K constitutive activation on the genes responsible for thyroid specification and function, we determined by quantitative real time PCR the expression levels of a battery of thyroid-relevant genes (Figure 3). Loss of Pten, as well as neoplastic transformation of Pten−/− thyrocytes, did not significantly or consistently change the expression of the three master genes involved in the specification and differentiation of the thyroid gland, namely Foxe1, Nkx2-1, and Pax8. Hyperplastic Pten−/− thyroids had normal mRNA levels of Tshr, Duox2, Slc5a5 (NIS), and slightly reduced expression of Tpo, Tg, and Duox1. Interestingly, we found that the expression of Tpo, Duox1, and Slc5a5 was significantly higher in thyroids from female mice, irrespective of Pten status, suggesting a role for estrogen in the control of the expression of these genes. Carcinomas and, to a lesser extent, adenomas developing in Pten−/− mice showed an increase in the expression of Tshr, as well as a reduction of mRNA levels for Duox1, Duox2 and, notably, Slc5a5.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

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.

Show MeSH
Related in: MedlinePlus