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

• Published in: Oncogene Vol. 29; no. 42; pp. 5678 - 5686
• Main Authors: Antico-Arciuch, V G, Dima, M, Liao, X-H, Refetoff, S, Di Cristofano, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-10-2010; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/208/2489/144/68; 631/67/1459/1843; Adenocarcinoma, Follicular - genetics; Adenocarcinoma, Follicular - metabolism; Adenocarcinoma, Follicular - pathology; Animals; Apoptosis; Biological and medical sciences; Blotting, Western; Cancer; Carcinoma; Care and treatment; Cell Biology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cyclin-Dependent Kinase Inhibitor p27 - biosynthesis; Endocrinopathies; Estrogen; Estrogens; Estrogens - metabolism; Female; Females; Fundamental and applied biological sciences. Psychology; Gender; Gene Expression; Gene Expression Profiling; Genetic aspects; Human Genetics; Incidence; Internal Medicine; Invasiveness; Kinases; Lesions; Male; Males; Malignant tumors; Medical sciences; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Mutant Strains; Molecular and cellular biology; Mutants; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Oncology; original-article; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Receptor Cross-Talk - physiology; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Rodents; Sex Characteristics; Sex differences; Thyrocytes; Thyroid cancer; Thyroid diseases; Thyroid Gland - metabolism; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Thyroid. Thyroid axis (diseases); Tumor suppressor genes; Tumors; United States; estrogen; thyroid cancer; Pten; Endocrinopathy; Thyroid diseases; Rodentia; Estrogen; Malignant tumor; Carcinogenesis; Follicular carcinoma; Ovarian hormone; Incidence; Vertebrata; Mammalia; Thyroid cancer; Mouse; Development; Female; Sex steroid hormone; Cancer; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.308

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.