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The Role of Tbx2 and Tbx3 in Mammary Development and Tumorigenesis

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Abstract

TBX2 and TBX3 are members of a family of genes encoding developmental transcription factors, characterized by a 200 amino acid DNA binding domain (T-box). Tbx2 and Tbx3 are closely related T-box proteins that have been implicated in development of a number of different tissues including the mammary gland. TBX3 is required for normal mammary development in mouse models and in patients with ulnar-mammary syndrome (UMS). In addition to a role in development, TBX2 and TBX3 have been implicated in tumor development through downregulation of the alternative reading frame (ARF) tumor suppressor and an associated bypass of senescence. Here we review the current information on the roles of Tbx2 and Tbx3 in mammary gland development and tumorigenesis.

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REFERENCES

  1. Dobrovolskaia-Zavadskaia N. Sur la mortification spontanee de la queue che la souris nouveau-nee et sur l'existence d'un caractere (facteur) herediaire "non viable". Crit Rev Soc Biol 1927;97:114–116.

    Google Scholar 

  2. Herrmann BG, Labeit S, Poustka A, King TR, Lehrach H. Cloning of the T gene required in mesoderm formation in the mouse. Nature 1990;343(6259):617–22.

    PubMed  Google Scholar 

  3. Pflugfelder GO, Roth H, Poeck B. A homology domain shared between Drosophila optomotor-blind and mouse Brachyury is involved in DNA binding. Biochem Biophys Res Commun 1992;186(2):918–25.

    PubMed  Google Scholar 

  4. Kispert A, HerrmannBG. The Brachyury gene encodes a novel DNA binding protein. Embo J 1993;12(8):3211–20.

    PubMed  Google Scholar 

  5. Agulnik SI, Garvey N, Hancock S, Ruvinsky I, Chapman DL, Agulnik I, et al. Evolution of mouse T-box genes by tandem duplication and cluster dispersion. Genetics 1996;144(1):249–54.

    PubMed  Google Scholar 

  6. Tada M, Smith JC. T-targets: clues to understanding the functions of T-box proteins. Dev Growth Differ 2001;43(1):1–11.

    Google Scholar 

  7. He M, Wen L, Campbell CE, Wu JY, Rao Y. Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. Proc Natl Acad Sci U S A 1999;96(18):10212–7.

    PubMed  Google Scholar 

  8. Carreira S, Dexter TJ, Yavuzer U, Easty DJ, Goding CR. Brachyury-related transcription factor Tbx2 and repression of the melanocyte-specific TRP-1 promoter. Mol Cell Biol 1998;18(9):5099–108.

    PubMed  Google Scholar 

  9. Carlson H, Ota S, Campbell CE, Hurlin PJ.Adominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Hum Mol Genet 2001;10(21):2403–13.

    PubMed  Google Scholar 

  10. Paxton C, Zhao H, Chin Y, Langner K, Reecy J. Murine Tbx2 contains domains that activate and repress gene transcription. Gene 2002;283(1-2):117–24.

    PubMed  Google Scholar 

  11. Chapman DL, Garvey N, Hancock S, Alexiou M, Agulnik SI, Gibson-Brown JJ, et al. Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev Dyn 1996;206(4):379–90.

    PubMed  Google Scholar 

  12. Gibson-Brown JJ, S IA, Silver LM, Papaioannou VE. Expression of T-box genes Tbx2-Tbx5 during chick organogenesis. Mech Dev 1998;74(1-2):165–9.

    PubMed  Google Scholar 

  13. Takabatake Y, Takabatake T, Takeshima K. Conserved and divergent expression of T-box genes Tbx2-Tbx5 in Xenopus. Mech Dev 2000;91(1-2):433–7.

    PubMed  Google Scholar 

  14. Papaioannou VE, Silver LM. The T-box gene family. Bioessays 1998;20(1):9–19.

    PubMed  Google Scholar 

  15. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol 2001;2(3):REVIEWS3005.1–3005.12

    Google Scholar 

  16. CobourneMT, Hardcastle Z, Sharpe PT. Sonic hedgehog regulates epithelial proliferation and cell survival in the developing tooth germ. J Dent Res 2001;80(11):1974–9.

    PubMed  Google Scholar 

  17. Gibson-Brown JJ, Agulnik SI, Chapman DL, Alexiou M, Garvey N, Silver LM, et al. Evidence of a role for T-box genes in the evolution of limb morphogenesis and the specification of forelimb/hindlimb identity. Mech Dev 1996;56(1-2):93–101.

    PubMed  Google Scholar 

  18. Capdevila J, Izpisua Belmonte JC. Patterning mechanisms controlling vertebrate limb development. Annu Rev Cell Dev Biol 2001;17:87–132.

    PubMed  Google Scholar 

  19. Sakakura T. Mammary embryogenesis. In: The Mammary Gland. Development, Regulation, and Function. 37–66. Ed. by M. C. Neville and C. W. Daniel Plenum Press, New York; 1987.

    Google Scholar 

  20. Veltmaat JM, Mailleux AA, Thiery JP, Bellusci S. Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation. Differentiation 2003;71(1):1–17.

    PubMed  Google Scholar 

  21. Mailleux AA, Spencer-Dene B, Dillon C, Ndiaye D, Savona-BaronC, ItohN, et al. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 2002;129(1):53–60.

    PubMed  Google Scholar 

  22. Davenport TG, Jerome-Majewska LA, Papaioannou VE. Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 2003;130(10):2263–73.

    PubMed  Google Scholar 

  23. Imagawa W, Pedchenko VK, Helber J, Zhang H. Hormone/growth factor interactions mediating epithelial/ stromal communication in mammary gland development and carcinogenesis. J Steroid BiochemMolBiol 2002;80(2):213–30.

    Google Scholar 

  24. Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell 2001;1(4):467–75.

    PubMed  Google Scholar 

  25. Cunha GR, Hom YK. Role of mesenchymal-epithelial interactions in mammary gland development. JMammary Gland Biol Neoplasia 1996;1(1):21–35.

    Google Scholar 

  26. Bamshad M, Le T, Watkins WS, Dixon ME, Kramer BE, Roeder AD, et al. The spectrum of mutations in TBX3: Genotype/ phenotype relationship in ulnar-mammary syndrome.Am J Hum Genet 1999;64(6):1550–62.

    PubMed  Google Scholar 

  27. Packham EA, Brook JD. T-box genes in human disorders.Hum Mol Genet 2003;12 Review Issue 1:R37–44.

    Google Scholar 

  28. Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, et al. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammarysyndrome. Nat Genet 1997;16(3):311–5.

    PubMed  Google Scholar 

  29. Xu X, Weinstein M, Li C, Naski M, Cohen RI, Ornitz DM, et al. Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 1998;125(4):753–65.

    PubMed  Google Scholar 

  30. Arman E, Haffner-Krausz R, Chen Y, Heath JK, Lonai P. Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. Proc Natl Acad Sci U S A 1998;95(9):5082–7.

    PubMed  Google Scholar 

  31. De Moerlooze L, Spencer-Dene B, Revest J, Hajihosseini M, Rosewell I, Dickson C. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis. Development 2000;127(3):483–92.

    PubMed  Google Scholar 

  32. Christiansen JH, Dennis CL, Wicking CA, Monkley SJ, Wilkinson DG, Wainwright BJ. Murine Wnt-11 and Wnt-12 have temporally and spatially restricted expression patterns during embryonic development. Mech Dev 1995;51(2-3):341–50.

    PubMed  Google Scholar 

  33. van Genderen C, Okamura RM, Farinas I, Quo RG, Parslow TG, Bruhn L, et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev 1994;8(22):2691–703.

    PubMed  Google Scholar 

  34. Andl T, Reddy ST, Gaddapara T, Millar SE. WNT signals are required for the initiation of hair follicle development. Dev Cell 2002;2(5):643–53.

    PubMed  Google Scholar 

  35. Takeuchi JK, Koshiba-Takeuchi K, Suzuki T, Kamimura M, Ogura K, Ogura T. Tbx5 and Tbx4 trigger limb initiation through activation of the Wnt/Fgf signaling cascade. Development 2003;130(12):2729–39.

    PubMed  Google Scholar 

  36. Kawakami Y, Capdevila J, Buscher D, Itoh T, Rodriguez Esteban C, Izpisua Belmonte JC. WNT signals control FGFdependent limb initiation and AER induction in the chick embryo. Cell 2001;104(6):891–900.

    PubMed  Google Scholar 

  37. FirnbergN, Neubuser A. FGF signaling regulates expression of Tbx2, Erm, Pea3, and Pax3 in the early nasal region. Dev Biol 2002;247(2):237–50.

    PubMed  Google Scholar 

  38. Wong K, Peng Y, Kung HF, He ML. Retina dorsal/ventral patterning by Xenopus TBX3. Biochem Biophys Res Commun 2002;290(2):737–42.

    PubMed  Google Scholar 

  39. Yamada M, Revelli JP, Eichele G, Barron M, Schwartz RJ. Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2. Dev Biol 2000;228(1):95–105.

    PubMed  Google Scholar 

  40. Tumpel S, Sanz-Ezquerro JJ, Isaac A, Eblaghie MC, Dobson J, Tickle C. Regulation of Tbx3 expression by anteroposterior signalling in vertebrate limb development. Dev Biol 2002;250(2):251–62.

    PubMed  Google Scholar 

  41. Takabatake Y, Takabatake T, Sasagawa S, Takeshima K. Conserved expression control and shared activity between cognate T-box genes Tbx2 and Tbx3 in connection with Sonic hedgehog signaling during Xenopus eye development. Dev Growth Differ 2002;44(4):257–71.

    PubMed  Google Scholar 

  42. Suzuki T, Takeuchi J, Koshiba-Takeuchi K, Ogura T. Tbx genes specify posterior digit identity through Shh andBMPsignaling. Dev Cell 2004;6(1):43–53.

    PubMed  Google Scholar 

  43. Sasagawa S, Takabatake T, Takabatake Y, Muramatsu T, Takeshima K. Axes establishment during eye morphogenesis in Xenopus by coordinate and antagonistic actions of BMP4, Shh, and RA. Genesis 2002;33(2):86–96.

    PubMed  Google Scholar 

  44. Gibson-Brown JJ, Agulnik SI, Silver LM, Niswander L, Papaioannou VE. Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development. Development 1998;125(13):2499–509.

    PubMed  Google Scholar 

  45. Daniel CW, Smith GH. The mammary gland: a model for development. J Mammary Gland Biol Neoplasia 1999;4(1): 3–8.

    Google Scholar 

  46. Gaudray P, Szepetowski P, Escot C, Birnbaum D, Theillet C. DNAamplification at 11q13 in human cancer: from complexity to perplexity. Mutat Res 1992;276(3):317–28.

    PubMed  Google Scholar 

  47. Borg A, Baldetorp B, Ferno M, Killander D, Olsson H, Sigurdsson H. ERBB2 amplification in breast cancer with a high rate of proliferation. Oncogene 1991;6(1):137–43.

    PubMed  Google Scholar 

  48. Berns EM, Foekens JA, van Staveren IL, van Putten WL, de Koning HY, Portengen H, et al. Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 1995;159(1):11–8.

    PubMed  Google Scholar 

  49. Wu G, Sinclair C, Hinson S, Ingle JN, Roche PC, Couch FJ. Structural analysis of the 17q22-23 amplicon identifies several independent targets of amplification in breast cancer cell lines and tumors. Cancer Res 2001;61(13):4951–5.

    PubMed  Google Scholar 

  50. Barlund M, Monni O, Kononen J, Cornelison R, Torhorst J, Sauter G, et al. Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. Cancer Res 2000;60(19):5340–4.

    PubMed  Google Scholar 

  51. Sinclair CS, Adem C, Naderi A, Soderberg CL, Johnson M, Wu K, et al. TBX2 is preferentially amplified in BRCA1-and BRCA2-related breast tumors. Cancer Res 2002;62(13):3587–91.

    PubMed  Google Scholar 

  52. Rouillard JM, Erson AE, Kuick R, Asakawa J, Wimmer K, Muleris M, et al. Virtual genome scan: a tool for restriction landmark-based scanning of the human genome. Genome Res 2001;11(8):1453–9.

    PubMed  Google Scholar 

  53. Wessendorf S, Schwaenen C, Kohlhammer H, Kienle D, Wrobel G, Barth TF, et al. Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray-based comparative genomic hybridization. Oncogene 2003;22(9):1425–9.

    PubMed  Google Scholar 

  54. Aubele M, Auer G, Braselmann H, Nahrig J, Zitzelsberger H, Quintanilla-Martinez L, et al. Chromosomal imbalances are associated with metastasis-free survival in breast cancer patients. Anal Cell Pathol 2002;24(2-3):77–87.

    PubMed  Google Scholar 

  55. Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK. Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis. Cancer Genet Cytogenet 1999;110(2):87–93.

    PubMed  Google Scholar 

  56. Brummelkamp TR, Kortlever RM, Lingbeek M, Trettel F, MacDonald ME, van Lohuizen M, et al. TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. J Biol Chem 2002;277(8):6567–72.

    PubMed  Google Scholar 

  57. Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev 2003;13(1):77–83.

    PubMed  Google Scholar 

  58. Jacobs JJ, KeblusekP, Robanus-Maandag E, KristelP, Lingbeek M, Nederlof PM, et al. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet 2000;26(3):291–9.

    PubMed  Google Scholar 

  59. Carlson H, Ota S, Song Y, Chen Y, Hurlin PJ. Tbx3 impinges on the p53 pathway to suppress apoptosis, facilitate cell transformation and block myogenic differentiation. Oncogene 2002;21(24):3827–35.

    PubMed  Google Scholar 

  60. Mason SL, Loughran O, La Thangue NB. p14(ARF) regulates E2F activity. Oncogene 2002;21(27):4220–30.

    PubMed  Google Scholar 

  61. Rocha S, Campbell KJ, Perkins ND. p53-and Mdm2-independent repression of NF-kappa B transactivation by the a tumor suppressor. Mol Cell 2003;12(1):15–25.

    PubMed  Google Scholar 

  62. Itahana K, Bhat KP, Jin A, Itahana Y, Hawke D, Kobayashi R, et al. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell 2003;12(5):1151–64.

    PubMed  Google Scholar 

  63. Kuo ML, Duncavage EJ, Mathew R, den Besten W, Pei D, Naeve D, et al. Arf induces p53-dependent and-independent antiproliferative genes. Cancer Res 2003;63(5):1046–53.

    PubMed  Google Scholar 

  64. Matsuda S, Rouault J, Magaud J, Berthet C. In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett 2001;497(2-3):67–72.

    PubMed  Google Scholar 

  65. Dominguez G, Silva J, Garcia JM, Silva JM, Rodriguez R, Munoz C, et al. Prevalence of aberrant methylation of p14ARF over p16INK4a in some human primary tumors. Mutat Res 2003;530(1-2):9–17.

    PubMed  Google Scholar 

  66. Silva J, Dominguez G, Silva JM, Garcia JM, Gallego I, Corbacho C, et al. Analysis of genetic and epigenetic processes that influence p14ARF expression in breast cancer. Oncogene 2001;20(33):4586–90.

    PubMed  Google Scholar 

  67. Guo-Chang F, Chu-Tse W. Transfer of p14ARF gene in drug-resistant human breast cancer MCF-7/Adr cells inhibits proliferation and reduces doxorubicin resistance. Cancer Lett 2000;158(2):203–10.

    PubMed  Google Scholar 

  68. Deng X, Kim M, VandierD, Jung YJ, Rikiyama T, Sgagias MK, et al. Recombinant adenovirus-mediated p14(ARF) overexpression sensitizes human breast cancer cells to cisplatin. Biochem Biophys Res Commun 2002;296(4):792–8.

    PubMed  Google Scholar 

  69. Chen J, Zhong Q, Wang J, Cameron RS, Borke JL, Isales CM, et al. Microarray analysis of Tbx2-directed gene expression: a possible role in osteogenesis. Mol Cell Endocrinol 2001;177(1-2):43–54.

    PubMed  Google Scholar 

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Rowley, M., Grothey, E. & Couch, F.J. The Role of Tbx2 and Tbx3 in Mammary Development and Tumorigenesis. J Mammary Gland Biol Neoplasia 9, 109–118 (2004). https://doi.org/10.1023/B:JOMG.0000037156.64331.3f

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