Akt1 deficiency delays tumor progression, vascular invasion, and distant metastasis in a murine model of thyroid cancer

• Published in: Oncogene Vol. 30; no. 42; pp. 4307 - 4315
• Main Authors: Saji, M, Narahara, K, McCarty, S K, Vasko, V V, La Perle, K M, Porter, K, Jarjoura, D, Lu, C, Cheng, S-Y, Ringel, M D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.10.2011; Nature Publishing Group
• Subjects: 631/67/322; 692/699/67/1459/1843; Adenoma - blood supply; Adenoma - enzymology; Age; AKT protein; AKT1 protein; AKT2 protein; Animal models; Animals; Apoptosis; Autopsy; Biological and medical sciences; Breast cancer; Carcinoma - blood supply; Carcinoma - enzymology; Carcinoma - secondary; Cell Biology; Cell physiology; Cell receptors; Cell structures and functions; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Development and progression; Endocrinopathies; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Knock-In Techniques; Hormone receptors; Hormones; Human Genetics; Hyperplasia; Internal Medicine; Invasiveness; Kinases; Lung; Lung Neoplasms - secondary; Malignant tumors; Medical sciences; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Miscellaneous; Molecular and cellular biology; Necropsy; Neovascularization, Pathologic - enzymology; Oncology; original-article; Physiological aspects; Protein kinases; Proto-Oncogene Proteins c-akt - deficiency; Proto-Oncogene Proteins c-akt - metabolism; Rodents; Thyroid cancer; Thyroid hormone receptors; Thyroid Neoplasms - blood supply; Thyroid Neoplasms - enzymology; Thyroid Neoplasms - pathology; Thyroid-stimulating hormone; Thyroid. Thyroid axis (diseases); Thyrotropin - blood; Tumors; United States; thyroid hormone receptor beta; thyrotropin; p27; PI3 kinase; gelsolin; Endocrinopathy; Animal model; Metastasis; Carcinogenesis; Tumor progression; Gelsolin; Tumor suppressor gene; Biological receptor; Enzyme; Transferases; Deficiency; Thyroid diseases; Rodentia; Malignant tumor; Vertebrata; Mammalia; Thyroid cancer; Mouse; Kinase; Thyroid hormone; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.136

Akt activation is common in progressive thyroid cancer. In breast cancer, Akt1 induces primary cancer growth, but is reported to inhibit metastasis in vivo in several model systems. In contrast, clinical and in vitro studies suggest a metastasis-promoting role for Akt1 in thyroid cancer. The goal of this study was to determine the functional role of Akt1 in thyroid cancer growth and metastatic progression in vivo using thyroid hormone receptor (TR) β PV/PV knock-in (PV) mice, which develop metastatic thyroid cancer. We crossed Akt1 −/− and PV mice and compared tumor development, local progression, metastasis and histology in TRβ PV/PV /Akt1 +/+ (PVPV-Akt1WT) and TRβ PV/PV /Akt1 −/− (PVPV-Akt1KO) mice. Mice were killed at 3, 6, 9, 12 and 15 months; necropsy was performed and serum thyroid stimulating hormone (TSH) was measured. Thyroid hyperplasia occurred in both groups beginning at 3 months; the thyroid size was greater in the PVPV-Akt1WT mice ( P <0.001). In comparison with PVPV-Akt1WT mice, thyroid cancer development was delayed in the PVPV-Akt1KO mice ( P =0.003) and the degree of tumor invasiveness was reduced. The PVPV-Akt1WT mice displayed pulmonary metastases at 12 and 15 months of age, by contrast PVPV-Akt1KO mice did not develop distant metastases at 15 months of age. Despite continued expression of Akt2 or Akt3, pAkt levels were decreased and there was evidence of reduced Akt effect on p27 in the PVPV-Akt1KO thyroids. TSH levels were similarly elevated in PV mice regardless of Akt1 expression. In conclusion, thyroid cancer development and progression in TR β PV/PV mice are Akt1-dependent, consistent with a tumor progression-promoting role in this murine thyroid cancer model.