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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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Aging thyroid-specific Pten−/− mice develop thyroid follicular carcinomas. a, Kaplan-Meyer analysis of the gender differences in survival of mutant mice. b, prevalence of thyroid lesions in Pten mutant mice. c, d, serum levels of TSH and T4 in aging mutant mice. Black circles in “d” correspond to mice with thyroid adenomas.
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Figure 1: Aging thyroid-specific Pten−/− mice develop thyroid follicular carcinomas. a, Kaplan-Meyer analysis of the gender differences in survival of mutant mice. b, prevalence of thyroid lesions in Pten mutant mice. c, d, serum levels of TSH and T4 in aging mutant mice. Black circles in “d” correspond to mice with thyroid adenomas.

Mentions: After one year of age, Pten mutant mice started showing signs of illness, and thyroid enlargement became macroscopically visible. At the end of the follow-up, we found that the female mutants had a significantly reduced lifespan(mean survival 73 weeks)compared to males(mean survival 83 weeks)(Figure 1a). We also analyzed the thyroid pathological features of a large group of these mice (n=54) between 8 and 12 months of age in order to further expand and validate our previously published more limited series (Yeager et al 2007). We found that, at this age, 52% of the females had developed thyroid follicular adenomas, compared to only 12% of the males(P=0.002)(Figure 1b). Remarkably, analysis of mice older than one year (n=34) revealed that 50% of the females, but only 35% of the males, had developed invasive and often metastatic thyroid follicular carcinomas (see below). When combined with the incidence of follicular adenomas, 93% of the females older than one year had developed neoplastic features, compared to only 65% of the males (P=0.05)(Figure 1b). These data establish the thyroid-specific Pten−/− strain as a physiologically and clinically relevant mouse model of follicular thyroid carcinoma. In addition, these mice represent a tool to further analyze the mechanisms responsible for the increased incidence of thyroid disorders in females.


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)

Aging thyroid-specific Pten−/− mice develop thyroid follicular carcinomas. a, Kaplan-Meyer analysis of the gender differences in survival of mutant mice. b, prevalence of thyroid lesions in Pten mutant mice. c, d, serum levels of TSH and T4 in aging mutant mice. Black circles in “d” correspond to mice with thyroid adenomas.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Aging thyroid-specific Pten−/− mice develop thyroid follicular carcinomas. a, Kaplan-Meyer analysis of the gender differences in survival of mutant mice. b, prevalence of thyroid lesions in Pten mutant mice. c, d, serum levels of TSH and T4 in aging mutant mice. Black circles in “d” correspond to mice with thyroid adenomas.
Mentions: After one year of age, Pten mutant mice started showing signs of illness, and thyroid enlargement became macroscopically visible. At the end of the follow-up, we found that the female mutants had a significantly reduced lifespan(mean survival 73 weeks)compared to males(mean survival 83 weeks)(Figure 1a). We also analyzed the thyroid pathological features of a large group of these mice (n=54) between 8 and 12 months of age in order to further expand and validate our previously published more limited series (Yeager et al 2007). We found that, at this age, 52% of the females had developed thyroid follicular adenomas, compared to only 12% of the males(P=0.002)(Figure 1b). Remarkably, analysis of mice older than one year (n=34) revealed that 50% of the females, but only 35% of the males, had developed invasive and often metastatic thyroid follicular carcinomas (see below). When combined with the incidence of follicular adenomas, 93% of the females older than one year had developed neoplastic features, compared to only 65% of the males (P=0.05)(Figure 1b). These data establish the thyroid-specific Pten−/− strain as a physiologically and clinically relevant mouse model of follicular thyroid carcinoma. In addition, these mice represent a tool to further analyze the mechanisms responsible for the increased incidence of thyroid disorders in females.

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