Akt Deficiency Delays Tumor Progression, Vascular Invasion, and Distant Metastases in a Murine Model of Thyroid Cancer Nih Public Access

Akt activation is common in progressive thyroid cancer. In breast cancer, Akt1 induced 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 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 sacrificed at 3, 6, 9, 12, and 15 months; necropsy was performed and serum TSH was measured. Thyroid hyperplasia occurred in both groups beginning at three 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 invasion 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 TRβ PV/PV mice are Akt1-dependent, consistent with a tumor progression-promoting role in this murine thyroid cancer model.

[1]  M. Willingham,et al.  Inhibition of mTORC1 signaling reduces tumor growth but does not prevent cancer progression in a mouse model of thyroid cancer. , 2010, Carcinogenesis.

[2]  N. Hay,et al.  Akt isoforms differentially regulate neutrophil functions. , 2010, Blood.

[3]  M. Willingham,et al.  Growth activation alone is not sufficient to cause metastatic thyroid cancer in a mouse model of follicular thyroid carcinoma. , 2010, Endocrinology.

[4]  Xuguang Zhu,et al.  Lessons from mouse models of thyroid cancer. , 2009, Thyroid : official journal of the American Thyroid Association.

[5]  Metin N. Gurcan,et al.  Pten in Stromal Fibroblasts Suppresses Mammary Epithelial Tumors , 2009, Nature.

[6]  G. Mills,et al.  Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. , 2009, Cancer research.

[7]  D. Helfman,et al.  RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility , 2009, Proceedings of the National Academy of Sciences.

[8]  M. Peppelenbosch,et al.  The Ubiquitin-Proteasome Pathway Mediates Gelsolin Protein Downregulation in Pancreatic Cancer , 2008, Molecular medicine.

[9]  M. Willingham,et al.  Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer. , 2007, Carcinogenesis.

[10]  G. Z. Cheng,et al.  Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. , 2007, Cancer research.

[11]  Caroline Kim,et al.  Gelsolin: a novel thyroid hormone receptor-beta interacting protein that modulates tumor progression in a mouse model of follicular thyroid cancer. , 2007, Endocrinology.

[12]  Bing-Hua Jiang,et al.  Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. , 2006, Cellular signalling.

[13]  M. Birnbaum,et al.  Opposing Roles for Akt1 and Akt2 in Rac/Pak Signaling and Cell Migration* , 2006, Journal of Biological Chemistry.

[14]  R. Shirkoohi,et al.  siRNA gelsolin knockdown induces epithelial‐mesenchymal transition with a cadherin switch in human mammary epithelial cells , 2006, International journal of cancer.

[15]  Hong Liu,et al.  Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Frederick Y. Wu,et al.  Reduction of cytosolic p27(Kip1) inhibits cancer cell motility, survival, and tumorigenicity. , 2006, Cancer research.

[17]  Sheue-yann Cheng,et al.  Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Brugge,et al.  Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial–mesenchymal transition , 2005, The Journal of cell biology.

[19]  V. Vasko,et al.  Akt1 contains a functional leucine-rich nuclear export sequence. , 2005, Biochemical and biophysical research communications.

[20]  V. Vasko,et al.  Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer , 2004, Journal of Medical Genetics.

[21]  P. Meltzer,et al.  Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma. , 2003, Carcinogenesis.

[22]  Alfonso Bellacosa,et al.  Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer , 2002, Nature Medicine.

[23]  Takashi Tsuruo,et al.  Akt-dependent Phosphorylation of p27Kip1Promotes Binding to 14-3-3 and Cytoplasmic Localization* , 2002, The Journal of Biological Chemistry.

[24]  K. Hruska,et al.  Phosphatidylinositol 3,4,5-Trisphosphate Directs Association of Src Homology 2-containing Signaling Proteins with Gelsolin* , 2001, The Journal of Biological Chemistry.

[25]  A. Fusco,et al.  Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models. , 2001, Endocrine reviews.

[26]  I. Roninson,et al.  Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. , 2001, Genes & development.

[27]  M. Saji,et al.  Overexpression and overactivation of Akt in thyroid carcinoma. , 2001, Cancer research.

[28]  M. Saji,et al.  Regulation of FRTL-5 thyroid cell growth by phosphatidylinositol (OH) 3 kinase-dependent Akt-mediated signaling. , 2001, Thyroid : official journal of the American Thyroid Association.

[29]  P. Pandolfi,et al.  Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse , 2001, Nature Genetics.

[30]  M. Willingham,et al.  Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Dumont,et al.  Phosphatidylinositol 3-kinase, protein kinase B and ribosomal S6 kinases in the stimulation of thyroid epithelial cell proliferation by cAMP and growth factors in the presence of insulin. , 2000, The Biochemical journal.

[32]  R. Weiss,et al.  Improved radioimmunoassay for measurement of mouse thyrotropin in serum: strain differences in thyrotropin concentration and thyrotroph sensitivity to thyroid hormone. , 1999, Thyroid : official journal of the American Thyroid Association.

[33]  Ximing J. Yang,et al.  The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. , 2006, Genes & development.

[34]  J. Slingerland,et al.  PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest , 2002, Nature Medicine.

[35]  K. Kaestner,et al.  Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). , 2001, Science.