Advertisement

Analysis of Thyroid Tumorigenesis in Xenograft Mouse Model

  • Xuguang Zhu
  • Sheue-Yann Cheng
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1801)

Abstract

Analysis of thyroid tumorigenesis in xenograft mouse model is important to study human thyroid cancer. Recent studies have made big strides toward understanding the molecular mechanisms by which thyroid hormone nuclear receptors (TR) act to maintain normal cellular functions in growth, differentiation, and development. Despite growing interest, the role of TR in oncogenesis remains to be fully elucidated. Two TR genes give rise to three major TR isoforms: TRα1, TRβ1, and TRβ2. These TR subtypes express in a tissue- and development-dependent manner. Research has been directed at understanding the mechanisms by which TR could mediate aberrant cellular signaling that contributes to oncogenesis, at dissecting possible distinct roles of TR isoforms in oncogenesis, and at the differential susceptibility of target tissues to the oncogenic actions of TR. This chapter gives a brief overview of the current undersatanding of known molecular oncogenic actions of TR. Here, we describe analysis of thyroid tumorigenesis used in interrogating the in vivo oncogenic actions of TR.

Key words

Thyroid hormone receptor Oncogenesis Thyroid tumorigenesis 

Notes

Acknowledgments

We regret any reference omissions due to length limitation. We wish to thank all colleagues and collaborators who have contributed to the work described in this review. The research described in this review by the authors and their colleagues at National Cancer Institute was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

Reference

  1. 1.
    Ali IU, Lidereau R, Callahan R (1989) Presence of two members of c-erbA receptor gene family (c-erbA beta and c-erbA2) in smallest region of somatic homozygosity on chromosome 3p21-p25 in human breast carcinoma. J Natl Cancer Inst 81(23):1815–1820CrossRefPubMedGoogle Scholar
  2. 2.
    Chen LC, Matsumura K, Deng G, Kurisu W, Ljung BM, Lerman MI, Waldman FM, Smith HS (1994) Deletion of two separate regions on chromosome 3p in breast cancers. Cancer Res 54(11):3021–3024PubMedGoogle Scholar
  3. 3.
    Gonzalez-Sancho JM, Garcia V, Bonilla F, Munoz A (2003) Thyroid hormone receptors/THR genes in human cancer. Cancer Lett 192(2):121–132CrossRefPubMedGoogle Scholar
  4. 4.
    Huber-Gieseke T, Pernin A, Huber O, Burger AG, Meier CA (1997) Lack of loss of heterozygosity at the c-erbA beta locus in gastrointestinal tumors. Oncology 54(3):214–219CrossRefPubMedGoogle Scholar
  5. 5.
    Leduc F, Brauch H, Hajj C, Dobrovic A, Kaye F, Gazdar A, Harbour JW, Pettengill OS, Sorenson GD, van den Berg A et al (1989) Loss of heterozygosity in a gene coding for a thyroid hormone receptor in lung cancers. Am J Hum Genet 44(2):282–287PubMedPubMedCentralGoogle Scholar
  6. 6.
    Sisley K, Curtis D, Rennie IG, Rees RC (1993) Loss of heterozygosity of the thyroid hormone receptor B in posterior uveal melanoma. Melanoma Res 3(6):457–461CrossRefPubMedGoogle Scholar
  7. 7.
    Futreal PA, Soderkvist P, Marks JR, Iglehart JD, Cochran C, Barrett JC, Wiseman RW (1992) Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphisms. Cancer Res 52(9):2624–2627PubMedGoogle Scholar
  8. 8.
    Yokota J, Yamamoto T, Miyajima N, Toyoshima K, Nomura N, Sakamoto H, Yoshida T, Terada M, Sugimura T (1988) Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by amplification of the v-erbA homologue. Oncogene 2(3):283–287PubMedGoogle Scholar
  9. 9.
    Dayton AI, Selden JR, Laws G, Dorney DJ, Finan J, Tripputi P, Emanuel BS, Rovera G, Nowell PC, Croce CM (1984) A human c-erbA oncogene homologue is closely proximal to the chromosome 17 breakpoint in acute promyelocytic leukemia. Proc Natl Acad Sci U S A 81(14):4495–4499CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lin KH, Shieh HY, Chen SL, Hsu HC (1999) Expression of mutant thyroid hormone nuclear receptors in human hepatocellular carcinoma cells. Mol Carcinog 26(1):53–61CrossRefPubMedGoogle Scholar
  11. 11.
    Silva JM, Dominguez G, Gonzalez-Sancho JM, Garcia JM, Silva J, Garcia-Andrade C, Navarro A, Munoz A, Bonilla F (2002) Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer. Oncogene 21(27):4307–4316.  https://doi.org/10.1038/sj.onc.1205534 CrossRefPubMedGoogle Scholar
  12. 12.
    Safer JD, Colan SD, Fraser LM, Wondisford FE (2001) A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma. Thyroid 11(3):281–291.  https://doi.org/10.1089/105072501750159750 CrossRefPubMedGoogle Scholar
  13. 13.
    Ando S, Sarlis NJ, Oldfield EH, Yen PM (2001) Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor. J Clin Endocrinol Metab 86(11):5572–5576.  https://doi.org/10.1210/jcem.86.11.7984 CrossRefPubMedGoogle Scholar
  14. 14.
    Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, Beug H, Vennstrom B (1986) The c-erb-a protein is a high-affinity receptor for thyroid hormone. Nature 324(6098):635–640.  https://doi.org/10.1038/324635a0 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Thormeyer D, Baniahmad A (1999) The v-erbA oncogene (review). Int J Mol Med 4(4):351–358PubMedGoogle Scholar
  16. 16.
    Yen PM, Ikeda M, Wilcox EC, Brubaker JH, Spanjaard RA, Sugawara A, Chin WW (1994) Half-site arrangement of hybrid glucocorticoid and thyroid hormone response elements specifies thyroid hormone receptor complex binding to DNA and transcriptional activity. J Biol Chem 269(17):12704–12709PubMedGoogle Scholar
  17. 17.
    Chen HW, Privalsky ML (1993) The erbA oncogene represses the actions of both retinoid X and retinoid a receptors but does so by distinct mechanisms. Mol Cell Biol 13(10):5970–5980CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Barlow C, Meister B, Lardelli M, Lendahl U, Vennstrom B (1994) Thyroid abnormalities and hepatocellular carcinoma in mice transgenic for v-erbA. EMBO J 13(18):4241–4250PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L, Carter TA, Kazlauskaite R, Pankratz DG, Wynshaw-Boris A, Refetoff S, Weintraub B, Willingham MC, Barlow C, Cheng S (2000) Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc Natl Acad Sci U S A 97(24):13209–13214.  https://doi.org/10.1073/pnas.230285997 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Suzuki H, Willingham MC, Cheng SY (2002) Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. Thyroid 12(11):963–969.  https://doi.org/10.1089/105072502320908295 CrossRefPubMedGoogle Scholar
  21. 21.
    Guigon CJ, Cheng SY (2009) Novel non-genomic signaling of thyroid hormone receptors in thyroid carcinogenesis. Mol Cell Endocrinol 308(1–2):63–69.  https://doi.org/10.1016/j.mce.2009.01.007 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Guigon CJ, Cheng SY (2009) Novel oncogenic actions of TRbeta mutants in tumorigenesis. IUBMB Life 61(5):528–536.  https://doi.org/10.1002/iub.180 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kim WG, Cheng SY (2013) Thyroid hormone receptors and cancer. Biochim Biophys Acta 1830(7):3928–3936.  https://doi.org/10.1016/j.bbagen.2012.04.002 CrossRefPubMedGoogle Scholar
  24. 24.
    Ying H, Suzuki H, Furumoto H, Walker R, Meltzer P, Willingham MC, Cheng SY (2003) Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma. Carcinogenesis 24(9):1467–1479.  https://doi.org/10.1093/carcin/bgg111 CrossRefPubMedGoogle Scholar
  25. 25.
    Guigon CJ, Kim DW, Zhu X, Zhao L, Cheng SY (2010) Tumor suppressor action of liganded thyroid hormone receptor beta by direct repression of beta-catenin gene expression. Endocrinology 151(11):5528–5536.  https://doi.org/10.1210/en.2010-0475 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Furuya F, Hanover JA, Cheng SY (2006) Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor. Proc Natl Acad Sci U S A 103(6):1780–1785.  https://doi.org/10.1073/pnas.0510849103 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Furuya F, Lu C, Willingham MC, Cheng SY (2007) Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer. Carcinogenesis 28(12):2451–2458.  https://doi.org/10.1093/carcin/bgm174 CrossRefPubMedGoogle Scholar
  28. 28.
    Kim CS, Vasko VV, Kato Y, Kruhlak M, Saji M, Cheng SY, Ringel MD (2005) AKT activation promotes metastasis in a mouse model of follicular thyroid carcinoma. Endocrinology 146(10):4456–4463.  https://doi.org/10.1210/en.2005-0172 CrossRefPubMedGoogle Scholar
  29. 29.
    Ying H, Furuya F, Zhao L, Araki O, West BL, Hanover JA, Willingham MC, Cheng SY (2006) Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta receptor inhibits mitotic progression. J Clin Invest 116(11):2972–2984.  https://doi.org/10.1172/JCI28598 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kim CS, Ying H, Willingham MC, Cheng SY (2007) The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer. Carcinogenesis 28(5):932–939.  https://doi.org/10.1093/carcin/bgl231 CrossRefPubMedGoogle Scholar
  31. 31.
    Kim WG, Guigon CJ, Fozzatti L, Park JW, Lu C, Willingham MC, Cheng SY (2012) SKI-606, an Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer. Clin Cancer Res 18(5):1281–1290.  https://doi.org/10.1158/1078-0432.CCR-11-2892 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kato Y, Ying H, Zhao L, Furuya F, Araki O, Willingham MC, Cheng SY (2006) PPARgamma insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-kappaB signaling pathway. Oncogene 25(19):2736–2747.  https://doi.org/10.1038/sj.onc.1209299 CrossRefPubMedGoogle Scholar
  33. 33.
    Araki O, Ying H, Furuya F, Zhu X, Cheng SY (2005) Thyroid hormone receptor beta mutants: dominant negative regulators of peroxisome proliferator-activated receptor gamma action. Proc Natl Acad Sci U S A 102(45):16251–16256.  https://doi.org/10.1073/pnas.0508556102 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Guigon CJ, Zhao L, Lu C, Willingham MC, Cheng SY (2008) Regulation of beta-catenin by a novel nongenomic action of thyroid hormone beta receptor. Mol Cell Biol 28(14):4598–4608.  https://doi.org/10.1128/MCB.02192-07 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kim CS, Furuya F, Ying H, Kato Y, Hanover JA, Cheng SY (2007) Gelsolin: a novel thyroid hormone receptor-beta interacting protein that modulates tumor progression in a mouse model of follicular thyroid cancer. Endocrinology 148(3):1306–1312.  https://doi.org/10.1210/en.2006-0923 CrossRefPubMedGoogle Scholar
  36. 36.
    Furumoto H, Ying H, Chandramouli GV, Zhao L, Walker RL, Meltzer PS, Willingham MC, Cheng SY (2005) An unliganded thyroid hormone beta receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis. Mol Cell Biol 25(1):124–135.  https://doi.org/10.1128/MCB.25.1.124-135.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Guigon CJ, Kim DW, Willingham MC, Cheng SY (2011) Mutation of thyroid hormone receptor-beta in mice predisposes to the development of mammary tumors. Oncogene 30(30):3381–3390.  https://doi.org/10.1038/onc.2011.50 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Parrilla R, Mixson AJ, McPherson JA, McClaskey JH, Weintraub BD (1991) Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain. J Clin Invest 88(6):2123–2130.  https://doi.org/10.1172/JCI115542 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Park JW, Zhao L, Willingham M, Cheng SY (2015) Oncogenic mutations of thyroid hormone receptor beta. Oncotarget 6(10):8115–8131.  https://doi.org/10.18632/oncotarget.3466 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Figueira AC, Saidemberg DM, Souza PC, Martinez L, Scanlan TS, Baxter JD, Skaf MS, Palma MS, Webb P, Polikarpov I (2011) Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange. Mol Endocrinol 25(1):15–31.  https://doi.org/10.1210/me.2010-0202 CrossRefPubMedGoogle Scholar
  41. 41.
    Wu SY, Cohen RN, Simsek E, Senses DA, Yar NE, Grasberger H, Noel J, Refetoff S, Weiss RE (2006) A novel thyroid hormone receptor-beta mutation that fails to bind nuclear receptor corepressor in a patient as an apparent cause of severe, predominantly pituitary resistance to thyroid hormone. J Clin Endocrinol Metab 91(5):1887–1895.  https://doi.org/10.1210/jc.2005-2428 CrossRefPubMedGoogle Scholar
  42. 42.
    Kim WG, Zhu X, Kim DW, Zhang L, Kebebew E, Cheng SY (2013) Reactivation of the silenced thyroid hormone receptor β gene expression delays thyroid tumor progression. Endocrinology 154(1):25–35. https://doi.org/10.1210/en.2012-1728 CrossRefPubMedGoogle Scholar
  43. 43.
    Kim WG, Zhao L, Kim DW, Willingham MC, Cheng SY (2014) Inhibition of tumorigenesis by the thyroid hormone receptor beta in xenograft models. Thyroid 24(2):260–269.  https://doi.org/10.1089/thy.2013.0054 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Park JW, Zhao L, Cheng SY (2013) Inhibition of estrogen-dependent tumorigenesis by the thyroid hormone receptor beta in xenograft models. Am J Cancer Res 3(3):302–311PubMedPubMedCentralGoogle Scholar
  45. 45.
    Graf T, Beug H (1983) Role of the v-erbA and v-erbB oncogenes of avian erythroblastosis virus in erythroid cell transformation. Cell 34(1):7–9CrossRefPubMedGoogle Scholar
  46. 46.
    Frykberg L, Palmieri S, Beug H, Graf T, Hayman MJ, Vennstrom B (1983) Transforming capacities of avian erythroblastosis virus mutants deleted in the erbA or erbB oncogenes. Cell 32(1):227–238CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaUSA

Personalised recommendations