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Helix-Loop-Helix Proteins in Mammary Gland Development and Breast Cancer

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Abstract

The basic helix-loop-helix (bHLH) family of transcription factors functions in the coordinated regulation of gene expression, cell lineage commitment, and cell differentiation in most mammalian tissues. Helix-loop-helix Id (Inhibitor of DNA binding) proteins are distinct from bHLH transcription factors in that they lack the basic domain necessary for DNA binding. Id proteins thus function as dominant negative regulators of bHLH transcription factors. The inhibition of bHLH factor activity by forced constitutive expression of Id proteins is closely associated with the inhibition of differentiation in a number of different cell types, including mammary epithelial cells. Moreover, recent literature suggests important roles of HLH proteins in many normal and transformed tissues, including mammary gland. Therefore, future directions for prognosis or therapeutic treatments of breast cancer may be able to exploit bHLH and Id genes as useful molecular targets. The purpose of this review is to summarize the evidence implicating HLH proteins in the regulation of normal and transformed mammary epithelial cell phenotypes.

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REFERENCES

  1. C. Murre, P. S. McCaw, and D. Baltimore (1989). A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56(5):777–783.

    PubMed  Google Scholar 

  2. M. E. Massari and C. Murre (2000). Helix-loop-helix proteins: Regulators of transcription in eucaryotic organisms. Mol. Cell. Biol. 20(2):429–440.

    PubMed  Google Scholar 

  3. S. Campuzano (2001). Emc, a negative HLH regulator with multiple functions in Drosophila development. Oncogene 20(58):8299–8307.

    PubMed  Google Scholar 

  4. Y. Yokota (2001). Id and development. Oncogene 20(58):8290–8298.

    PubMed  Google Scholar 

  5. W. R. Atchley and W. M. Fitch (1997). A natural classification of the basic helix-loop-helix class of transcription factors. Proc. Natl. Acad. Sci. U.S.A. 94(10):5172–5176.

    PubMed  Google Scholar 

  6. I. Engel and C. Murre (2001). The function of E-and Id proteins in lymphocyte development. Nat. Rev. Immunol. 1(3):193–199.

    PubMed  Google Scholar 

  7. J. D. Norton, R. W. Deed, G. Craggs, and F. Sablitzky (1998). Id helix-loop-helix proteins in cell growth and differentiation. Trends. Cell. Biol. 8(2):58–65.

    PubMed  Google Scholar 

  8. R. Benezra (2001). The Id proteins: Targets for inhibiting tumor cells and their blood supply. Biochim. Biophys. Acta. 1551(2):F39-F47.

    PubMed  Google Scholar 

  9. D. Lyden, A. Z. Young, D. Zagzag, W. Yan, W. Gerald, R. O'Reilly, B. L. Bader, R. O. Hynes, Y. Zhuang, K. Manova, R. Benezra (1999). Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401(6754):670–677.

    PubMed  Google Scholar 

  10. Y. Jen, K. Manova, and R. Benezra (1996). Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis. Dev Dyn. 207(3):235–252.

    PubMed  Google Scholar 

  11. J. D. Norton (2000). ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J. Cell. Sci. 113(Pt. 22):3897–3905.

    PubMed  Google Scholar 

  12. R. Rivera and C. Murre (2001). The regulation and function of the Id proteins in lymphocyte development. Oncogene 20(58):8308–8316.

    PubMed  Google Scholar 

  13. Y. Yokota and S. Mori (2002). Role of Id family proteins in growth control. J. Cell. Physiol. 190(1):21–28.

    PubMed  Google Scholar 

  14. R. Benezra, S. Rafii, and D. Lyden (2001). The Id proteins and angiogenesis. Oncogene 20(58):8334–8341.

    PubMed  Google Scholar 

  15. Z. Zebedee and E. Hara (2001). Id proteins in cell cycle control and cellular senescence. Oncogene 20(58):8317–8325.

    PubMed  Google Scholar 

  16. P. J. Andres-Barquin, M. C. Hernandez, and M. A. Israel (2000). Id genes in nervous system development. Histol. Histopathol. 15(2):603–618.

    PubMed  Google Scholar 

  17. C. Murre, G. Bain, M. A. van Dijk, I. Engel, B. A. Furnari, M. E. Massari, J. R. Matthews, M. W. Quong, R. R. Rivera, and M. H. Stuiver (1994). Structure and function of helix-loop-helix proteins. Biochim. Biophys. Acta 1218(2):129–135.

    PubMed  Google Scholar 

  18. A. Ephrussi, G. M. Church, S. Tonegawa, W. Gilbert (1985). B lineage—Specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science 227(4683):134–140.

    PubMed  Google Scholar 

  19. R. Benezra, R. L. Davis, D. Lockshon, D. L. Turner, and H. Weintraub (1990). The protein Id: A negative regulator of helix-loop-helix DNA binding proteins. Cell 61(1):49–59.

    PubMed  Google Scholar 

  20. H. M. Ellis, D. R. Spann, and J. W. Posakony (1990). Extramacrochaetae, a negative regulator of sensory organ development in Drosophila, defines a new class of helix-loop-helix proteins. Cell 61(1):27–38.

    PubMed  Google Scholar 

  21. A. Lasorella, T. Uo, and A. Iavarone (2001). Id proteins at the cross-road of development and cancer. Oncogene 20(58):8326–8333.

    PubMed  Google Scholar 

  22. J. P. Coppe, A. P. Smith, and P. Y. Desprez (2003). Id proteins in epithelial cells. Exp. Cell. Res. 285(1):131–145.

    PubMed  Google Scholar 

  23. L. Hennighausen and G. W. Robinson (1998). Think globally, act locally: The making of a mouse mammary gland. Genes. Dev. 12(4):449–455.

    PubMed  Google Scholar 

  24. R. Strange, T. Metcalfe, L. Thackray, and M. Dang (2001). Apoptosis in normal and neoplastic mammary gland development. Microsc. Res. Tech. 52(2):171–181.

    PubMed  Google Scholar 

  25. V. Djonov, A. C. Andres, and A. Ziemiecki (2001). Vascular remodelling during the normal and malignant life cycle of the mammary gland. Microsc. Res. Tech. 52(2):182–189.

    PubMed  Google Scholar 

  26. J. Russo, Y. F. Hu, I. D. Silva, and I. H. Russo (2001). Cancer risk related to mammary gland structure and development. Microsc. Res. Tech. 52(2):204–223.

    PubMed  Google Scholar 

  27. A. Clamp, S. Danson, and M. Clemons (2002). Hormonal risk factors for breast cancer: Identification, chemoprevention, and other intervention strategies. Lancet. Oncol. 3(10):611–619.

    PubMed  Google Scholar 

  28. P. Henthorn, M. Kiledjian, and T. Kadesch (1990). Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Science 247(4941):467–470.

    PubMed  Google Scholar 

  29. P. Dias, M. Dilling, and P. Houghton (1994). The molecular basis of skeletal muscle differentiation. Semin. Diagn. Pathol. 11(1):3–14.

    PubMed  Google Scholar 

  30. S. Desiderio (1995). Lymphopoiesis. Transcription factors controlling B-cell development. Curr. Biol. 5(6):605–608.

    PubMed  Google Scholar 

  31. M. H. Farah, J. M. Olson, H. B. Sucic, R. I. Hume, S. J. Tapscott, and D. L. Turner (2000). Generation of neurons by transient expression of neural bHLH proteins in mammalian cells. Development 127(4):693–702.

    PubMed  Google Scholar 

  32. J. Chaudhary, A. S. Cupp, and M. K. Skinner (1997). Role of basic-helix-loop-helix transcription factors in Sertoli cell differentiation: Identification of an E-box response element in the transferrin promoter. Endocrinology. 138(2):667–675.

    PubMed  Google Scholar 

  33. S. T. Park, G. P. Nolan, and X. H. Sun (1999). Growth inhibition and apoptosis due to restoration of E2A activity in T cell acute lymphoblastic leukemia cells. J. Exp. Med. 189(3):501–508.

    PubMed  Google Scholar 

  34. H. Weintraub, R. Davis, S. Tapscott, M. Thayer, M. Krause, R. Benezra, T. K. Blackwell, D. Turner, R. Rupp, S. Hollenberg, Y. Zhuang and A. Lassar. (1991) The myoD gene family: Nodal point during specification of the muscle cell lineage. Science 251(4995):761–766.

    PubMed  Google Scholar 

  35. E. N. Olson (1990). MyoD family: A paradigm for development? Genes Dev. 4(9):1454–1461.

    PubMed  Google Scholar 

  36. R. Kageyama, M. Ishibashi, K. Takebayashi, and K. Tomita (1997). bHLH transcription factors and mammalian neuronal differentiation. Int. J. Biochem. Cell. Biol. 29(12):1389–1399.

    PubMed  Google Scholar 

  37. F. J. Naya, H. P. Huang, Y. Qiu, H. Mutoh, F. J. DeMayo, A. B. Leiter, and M. J. Tsai (1997). Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 11(18):2323–2334.

    PubMed  Google Scholar 

  38. D. Srivastava (1999). HAND proteins: Molecular mediators of cardiac development and congenital heart disease. Trends Cardiovasc Med. 9(1/2):11–18.

    PubMed  Google Scholar 

  39. R. Kageyama, Y. Sasai, C. Akazawa, M. Ishibashi, K. Takebayashi, C. Shimizu, K. Tomita, and S. Nakanishi (1995). Regulation of mammalian neural development by helix-loop-helix transcription factors. Crit. Rev. Neurobiol. 9(2/3):177–188.

    PubMed  Google Scholar 

  40. D. B. Spicer, J. Rhee, W. L. Cheung, and A. B. Lassar (1996). Inhibition of myogenic bHLH and MEF2 transcription factors by the bHLH protein Twist. Science. 272(5267):1476–1480.

    PubMed  Google Scholar 

  41. C. Lemercier, R. Q. To, R. A. Carrasco, and S. F. Konieczny (1998). The basic helix-loop-helix transcription factor Mist1 functions as a transcriptional repressor of myoD. EMBO J. 17(5):1412–1422.

    PubMed  Google Scholar 

  42. C. L. Pin, A. C. Bonvissuto, and S. F. Konieczny (2000). Mist1 expression is a common link among serous exocrine cells exhibiting regulated exocytosis. Anat. Rec. 259(2):157–167.

    PubMed  Google Scholar 

  43. R. A. Shivdasani, E. L. Mayer, and S. H. Orkin (1995). Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 373(6513):432–434.

    PubMed  Google Scholar 

  44. I. Vastrik, T. P. Makela, P. J. Koskinen, J. Klefstrom, and K. Alitalo (1994). Myc protein: Partners and antagonists. Crit. Rev. Oncog. 5(1):59–68.

    PubMed  Google Scholar 

  45. F. Javaux, A. Donda, G. Vassart, and D. Christophe (1991). Cloning and sequence analysis of TFE, a helix-loop-helix transcription factor able to recognize the thyroglobulin gene promoter in vitro. Nucleic. Acids. Res. 19(5):1121–1127.

    PubMed  Google Scholar 

  46. M. S. Brown and J. L. Goldstein (1997). The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 89(3):331–340.

    PubMed  Google Scholar 

  47. P. J. Hurlin, D. E. Ayer, C. Grandori, and R. N. Eisenman (1994). The Max transcription factor network: Involvement of Mad in differentiation and an approach to identification of target genes. Cold Spring Harb. Symp. Quant. Biol. 59:109–116.

    PubMed  Google Scholar 

  48. P. Muller, S. Kietz, J. A. Gustafsson, and A. Strom (2002). The anti-estrogenic effect of all-trans-retinoic acid on the breast cancer cell line MCF-7 is dependent on HES-1 expression. J. Biol. Chem. 277(32):28376–28379.

    PubMed  Google Scholar 

  49. A. M. Henderson, S. J. Wang, A. C. Taylor, M. Aitkenhead, and C. C. Hughes (2001). The basic helix-loop-helix transcription factor HESR1 regulates endothelial cell tube formation. J. Biol. Chem. 276(9):6169–6176.

    PubMed  Google Scholar 

  50. C. Qin, C. Wilson, C. Blancher, M. Taylor, S. Safe, and A. L. Harris (2001). Association of ARNT splice variants with estrogen receptor-negative breast cancer, poor induction of vascular endothelial growth factor under hypoxia, and poor prognosis. Clin. Cancer. Res. 7(4):818–823.

    PubMed  Google Scholar 

  51. O. Hankinson (1995). The aryl hydrocarbon receptor complex. Annu. Rev. Pharmacol. Toxicol. 35:307–340.

    PubMed  Google Scholar 

  52. H. I. Swanson and C. A. Bradfield (1993). The AH-receptor: Genetics, structure and function. Pharmacogenetics 3(5):213–230.

    PubMed  Google Scholar 

  53. G. Semenza (2002). Signal transduction to hypoxia-inducible factor 1. Biochem. Pharmacol. 64(5/6):993–998.

    PubMed  Google Scholar 

  54. R. W. Deed, M. Jasiok, and J. D. Norton (1994). Nucleotide sequence of the cDNA encoding human helix-loop-helix Id-1 protein: Identification of functionally conserved residues common to Id proteins. Biochim. Biophys. Acta. 1219(1):160–162.

    PubMed  Google Scholar 

  55. X. H. Sun, N. G. Copeland, N. A. Jenkins, and D. Baltimore (1991). Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol. Cell. Biol. 11(11):5603–5611.

    PubMed  Google Scholar 

  56. J. Biggs, E. V. Murphy, and M. A. Israel (1992). A human Id-like helix-loop-helix protein expressed during early development. Proc. Natl. Acad. Sci. U.S.A. 89(4):1512–1516.

    PubMed  Google Scholar 

  57. B. A. Christy, L. K. Sanders, L. F. Lau, N. G. Copeland, N. A. Jenkins, and D. Nathans (1991). An Id-related helix-loop-helix protein encoded by a growth factor-inducible gene. Proc. Natl. Acad. Sci. U.S.A. 88(5):1815–1819.

    PubMed  Google Scholar 

  58. W. Ellmeier, A. Aguzzi, E. Kleiner, R. Kurzbauer, and A. Weith (1992). Mutually exclusive expression of a helix-loop-helix gene and N-myc in human neuroblastomas and in normal development. EMBO J. 11(7):2563–2571.

    PubMed  Google Scholar 

  59. V. Riechmann, I. van Cruchten and F. Sablitzky (1994). The expression pattern of Id4, a novel dominant negative helix-loop-helix protein, is distinct from Id1, Id2 and Id3. Nucleic. Acids. Res. 22(5):749–755.

    PubMed  Google Scholar 

  60. A. Pagliuca, P. C. Bartoli, S. Saccone, G. Della Valle, and L. Lania (1995). Molecular cloning of ID4, a novel dominant negative helix-loop-helix human gene on chromosome 6p21.3-p22. Genomics 27(1):200–203.

    PubMed  Google Scholar 

  61. R. Wilson and T. Mohun (1995). XIdx, a dominant negative regulator of bHLH function in early Xenopus embryos. Mech. Dev. 49(3):211–222.

    PubMed  Google Scholar 

  62. S. Sawai and J. A. Campos-Ortega (1997). A zebrafish Id homologue and its pattern of expression during embryogenesis. Mech. Dev. 65(1/2):175–185.

    PubMed  Google Scholar 

  63. M. Shirakata, F. K. Friedman, Q. Wei, and B. M. Paterson (1993). Dimerization specificity of myogenic helix-loop-helix DNA-binding factors directed by nonconserved hydrophilic residues. Genes Dev. 7(12A):2456–2470.

    PubMed  Google Scholar 

  64. A. N. Goldfarb, K. Lewandowska, and C. A. Pennell (1998). Identification of a highly conserved module in E proteins required for in vivo helix-loop-helix dimerization. J. Biol. Chem. 273(5):2866–2873.

    PubMed  Google Scholar 

  65. P. C. Ma, M. A. Rould, H. Weintraub, and C. O. Pabo (1994). Crystal structure of MyoD bHLH domain-DNA complex: Perspectives on DNA recognition and implications for transcriptional activation. Cell. 77(3):451–459.

    PubMed  Google Scholar 

  66. T. Ellenberger, D. Fass, M. Arnaud, and S. C. Harrison (1994). Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer. Genes Dev. 8(8):970–980.

    PubMed  Google Scholar 

  67. S. Pesce and R. Benezra (1993). The loop region of the helix-loop-helix protein Id1 is critical for its dominant negative activity. Mol. Cell. Biol. 13(12):7874–7880.

    PubMed  Google Scholar 

  68. J. Wibley, R. Deed, M. Jasiok, K. Douglas, and J. Norton (1996). A homology model of the Id-3 helix-loop-helix domain as a basis for structure–function predictions. Biochim. Biophys. Acta. 1294(2):138–146.

    PubMed  Google Scholar 

  69. E. Hara, M. Hall, and G. Peters (1997). Cdk2-dependent phosphorylation of Id2 modulates activity of E2A-related transcription factors. EMBO J. 16(2):332–342.

    PubMed  Google Scholar 

  70. R. W. Deed, E. Hara, G. T. Atherton, G. Peters, and J. D. Norton (1997). Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation. Mol. Cell. Biol. 17(12):6815–6821.

    PubMed  Google Scholar 

  71. R. W. Deed, S. Armitage, M. Brown, and J. D. Norton (1996). Regulation of Id-HLH transcription factor function in third messenger signalling. Biochem. Soc. Trans. 24(1):5S.

    PubMed  Google Scholar 

  72. M. A. Bounpheng, J. J. Dimas, S. G. Dodds, and B. A. Christy (1999). Degradation of Id proteins by the ubiquitin-proteasome pathway. FASEB J. 13(15):2257–2264.

    PubMed  Google Scholar 

  73. G. Anand, X. Yin, A. K. Shahidi, L. Grove, and E. V. Prochownik (1997). Novel regulation of the helix-loop-helix protein Id1 by S5a, a subunit of the 26 S proteasome. J. Biol. Chem. 272(31):19140–19151.

    PubMed  Google Scholar 

  74. R. W. Deed, S. Armitage, and J. D. Norton (1996). Nuclear localization and regulation of Id protein through an E protein-mediated chaperone mechanism. J. Biol. Chem. 271(39):23603–23606.

    PubMed  Google Scholar 

  75. E. Hara, T. Yamaguchi, H. Nojima, T. Ide, J. Campisi, H. Okayama, and K. Oda (1994). Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J. Biol. Chem. 269(3):2139–2145.

    PubMed  Google Scholar 

  76. J. O. Nehlin, E. Hara, W. L. Kuo, C. Collins, J. Campisi (1997). Genomic organization, sequence, and chromosomal localization of the human helix-loop-helix Id1 gene. Biochem. Biophys. Res. Commun. 231(3):628–634.

    PubMed  Google Scholar 

  77. R. W. Deed, T. Hirose, E. L. Mitchell, M. F. Santibanez-Koref, and J. D. Norton (1994). Structural organisation and chromosomal mapping of the human Id-3 gene. Gene. 151(1/2):309–314.

    PubMed  Google Scholar 

  78. R. W. Deed, M. Jasiok, and J. D. Norton (1996). Attenuated function of a variant form of the helix-loop-helix protein, Id-3, generated by an alternative splicing mechanism. FEBS Lett. 393(1):113–116.

    PubMed  Google Scholar 

  79. M. Kurabayashi, R. Jeyaseelan, and L. Kedes (1993). Two distinct cDNA sequences encoding the human helix-loop-helix protein Id2. Gene. 133(2):305–306.

    PubMed  Google Scholar 

  80. M. V. Barone, R. Pepperkok, F. A. Peverali, and L. Philipson (1994). Id proteins control growth induction in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 91(11):4985–4988.

    PubMed  Google Scholar 

  81. P. H. King, T. D. Levine, R. T. FremeauJr., and J. D. Keene (1994). Mammalian homologs of Drosophila ELAV localized to a neuronal subset can bind in vitro to the 3′ UTR of mRNA encoding the Id transcriptional repressor. J. Neurosci. 14(4):1943–1952.

    PubMed  Google Scholar 

  82. J. D. Keene (2001). Ribonucleoprotein infrastructure regulating the flow of genetic information between the genome and the proteome. Proc. Natl. Acad. Sci. U.S.A. 98(13):7018–7024.

    PubMed  Google Scholar 

  83. J. Singh, Y. Itahana, S. Parrinello, K. Murata, and P. Y. Desprez (2001). Molecular cloning and characterization of a zinc finger protein involved in Id-1-stimulated mammary epithelial cell growth. J. Biol. Chem. 276(15):11852–11858.

    PubMed  Google Scholar 

  84. S. Parrinello, C. Q. Lin, K. Murata, Y. Itahana, J. Singh, A. Krtolica, J. Campisi, and P. Y. Desprez (2001). Id-1, ITF-2, and Id-2 comprise a network of helix-loop-helix proteins that regulate mammary epithelial cell proliferation, differentiation, and apoptosis. J. Biol. Chem. 276(42):39213–39219.

    PubMed  Google Scholar 

  85. P. Y. Desprez, C. Q. Lin, N. Thomasset, C. J. Sympson, M. J. Bissell, and J. Campisi (1998). A novel pathway for mammary epithelial cell invasion induced by the helix-loop-helix protein Id-1. Mol. Cell. Biol. 18(8):4577–4588.

    PubMed  Google Scholar 

  86. P. Y. Desprez, E. Hara, M. J. Bissell, and J. Campisi (1995). Suppression of mammary epithelial cell differentiation by the helix-loop-helix protein Id-1. Mol. Cell. Biol. 15(6):3398–3404.

    PubMed  Google Scholar 

  87. P. L. Woo, A. Cercek, P. Y. Desprez, and G. L. Firestone (2000). Involvement of the helix-loop-helix protein Id-1 in the glucocorticoid regulation of tight junctions in mammary epithelial cells. J. Biol. Chem. 275(37):28649–28658.

    PubMed  Google Scholar 

  88. K. Miyoshi, B. Meyer, P. Gruss, Y. Cui, J. P. Renou, F. V. Morgan, G. H. Smith, M. Reichenstein, M. Shani, L. Hennighausen, and G. W. Robinson (2002). Mammary epithelial cells are not able to undergo pregnancy-dependent differentiation in the absence of the helix-loop-helix inhibitor Id2. Mol. Endocrinol. 16(12):2892–2901.

    PubMed  Google Scholar 

  89. S. Mori, S. I. Nishikawa, and Y. Yokota (2000). Lactation defect in mice lacking the helix-loop-helix inhibitor Id2. EMBO J. 19(21):5772–5781.

    PubMed  Google Scholar 

  90. C. Q. Lin, J. Singh, K. Murata, Y. Itahana, S. Parrinello, S. H. Liang, C. E. Gillett, J. Campisi, and P. Y. Desprez (2000). A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells. Cancer. Res. 60(5):1332–1340.

    PubMed  Google Scholar 

  91. J. Singh, K. Murata, Y. Itahana, and P. Y. Desprez (2002). Constitutive expression of the Id-1 promoter in human metastatic breast cancer cells is linked with the loss of NF-1/Rb/HDAC-1 transcription repressor complex. Oncogene 21(12):1812–1822.

    PubMed  Google Scholar 

  92. S. F. Schoppmann, M. Schindl, G. Bayer, K. Aumayr, J. Dienes, R. Horvat, M. Rudas, M. Gnant, R. Jakesz, and P. Birner (2003). Overexpression of Id-1 is associated with poor clinical outcome in node negative breast cancer. Int. J. Cancer. 104(6):677–682.

    PubMed  Google Scholar 

  93. J. H. Clement, N. Marr, A. Meissner, M. Schwalbe, W. Sebald, K. O. Kliche, K. Hoffken, S. Wolfl (2000). Bone morphogenetic protein 2 (BMP-2) induces sequential changes of Id gene expression in the breast cancer cell line MCF-7. J. Cancer Res. Clin. Oncol. 126(5):271–279.

    PubMed  Google Scholar 

  94. S. Fong, Y. Itahana, T. Sumida, J. Singh, J. P. Coppe, Y. Liu, P. C. Richards, J. L. Bennington, N. M. Lee, R. J. Debs, and P. Y. Desprez (manuscript submitted for publication) Id-1 is a new molecular target in breast cancer cell invasion and metastasis.

  95. Y. Itahana, J. Singh, T. Sumida, J. P. Coppe, J. L. Bennington, and P. Y. Desprez (manuscript submitted for publication). Role of Id-2 in the maintenance of a differentiated and non-invasive phenotype in breast cancer cells.

  96. C. Beger, L. N. Pierce, M. Kruger, E. G. Marcusson, J. M. Robbins, P. Welcsh, P. J. Welch, K. Welte, M. C. King, J. R. Barber, and F. Wong-Staal (2001). Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. Proc. Natl. Acad. Sci. U.S.A. 98(1):130–135.

    PubMed  Google Scholar 

  97. L. Hennighausen and G. W. Robinson (2001). Signaling pathways in mammary gland development. Dev. Cell. 1(4):467–475.

    PubMed  Google Scholar 

  98. C. Schmidhauser, M. J. Bissell, C. A. Myers, and G. F. Casperson (1990). Extracellular matrix and hormones transcriptionally regulate bovine beta-casein 5′ sequences in stably transfected mouse mammary cells. Proc. Natl. Acad. Sci. U.S.A. 87(23):9118–9122.

    PubMed  Google Scholar 

  99. P. Y. Desprez, C. Roskelley, J. Campisi, and M. J. Bissell (1993). Isolation of functional cell lines from a mouse mammary cell strain: The importance of basement membrane and cell-cell interaction. Mol. Cell. Differ. 1:99–110.

    Google Scholar 

  100. C. D. Roskelley, P. Y. Desprez, and M. J. Bissell (1994). Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. Proc. Natl. Acad. Sci. U.S.A. 91(26):12378–12382.

    PubMed  Google Scholar 

  101. N. Uehara, Y. C. Chou, J. J. Galvez, P. de-Candia, R. D. Cardiff, R. Benezra, and G. Shyamala (2003). Id-1 is not expressed in the luminal epithelial cells of mammary glands, Breast. Cancer Res. 5:R25-R29.

    PubMed  Google Scholar 

  102. I. S. Skerjanc, J. Truong, P. Filion, and M. W. McBurney (1996). A splice variant of the ITF-2 transcript encodes a transcription factor that inhibits MyoD activity. J. Biol. Chem. 271(7):3555–3561.

    PubMed  Google Scholar 

  103. K. Neuman, H. O. Nornes, and T. Neuman (1995). Helix-loop-helix transcription factors regulate Id2 gene promoter activity. FEBS Lett. 374(2):279–283.

    PubMed  Google Scholar 

  104. A. Swarbrick, L. J. Hunter, C. S. Lee, C. M. Sergio, R. L. Sutherlan, and E. A. Musgrove Id1 is a critical target of c-myc in breast cancer cells. Molecular Biology of the Cell, 42nd American Society for Cell Biology Annual Meeting, Abstract 2438.

  105. R. J. Akhurst and R. Derynck (2001). TGF-beta signaling in cancer—A double-edged sword. Trends Cell Biol. 11(11):S44-S51.

    PubMed  Google Scholar 

  106. T. Ogata, J. M. Wozney, R. Benezra, and M. Noda (1993). Bone morphogenetic protein 2 transiently enhances expression of a gene, Id (inhibitor of differentiation), encoding a helix-loop-helix molecule in osteoblast-like cells. Proc. Natl. Acad. Sci. U.S.A. 90(19):9219–9222.

    PubMed  Google Scholar 

  107. T. Katagiri, A. Yamaguchi, M. Komaki, E. Abe, N. Takahashi, T. Ikeda, V. Rosen, J. M. Wozney, A. Fujisawa-Sehara, and T. Suda (1994). Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J. Cell. Biol. 127(6, Pt. 1):1755–1766.

    PubMed  Google Scholar 

  108. O. Korchynskyi and P. ten Dijke (2002). Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J. Biol. Chem. 277(7):4883–4891.

    PubMed  Google Scholar 

  109. T. Lopez-Rovira, E. Chalaux, J. Massague, J. L. Rosa, and F. Ventura (2002). Direct binding of Smad1 and Smad4 to two distinct motifs mediates bone morphogenetic protein-specific transcriptional activation of Id1 gene. J. Biol. Chem. 277(5):3176–3185.

    PubMed  Google Scholar 

  110. P. L. Davis, A. Miron, L. M. Andersen, J. D. Iglehart, and J. R. Marks (1999). Isolation and initial characterization of the BRCA2 promoter. Oncogene 18(44):6000–6012.

    PubMed  Google Scholar 

  111. F. T. Kolligs, M. T. Nieman, I. Winer, G. Hu, D. Van Mater, Y. Feng, I. M. Smith, R. Wu, Y. Zhai, K. R. Cho, and E. R. Fearon (2002). ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. Cancer Cell 1(2):145–155.

    PubMed  Google Scholar 

  112. P. Polakis (2000). Wnt signalling and cancer. Genes Dev. 14:1837–1851.

    PubMed  Google Scholar 

  113. J. S. Michaelson and P. Leder (2001). Beta-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland. Oncogene 20(37):5093–5099.

    PubMed  Google Scholar 

  114. R. C. Gallagher, T. Hay, V. Meniel, C. Naughton, T. J. Anderson, H. Shibata, M. Ito, H. Clevers, T. Noda, O. J. Sansom, J. O. Mason, and A. R. Clarke (2002). Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency. Oncogene 21(42):6446–6457.

    PubMed  Google Scholar 

  115. M. Bien and H. Clevers (2000). Linking colorectal cancer to Wnt signaling. Cell 103(2):311–320.

    PubMed  Google Scholar 

  116. J. P. Thiery (2002). Epithelial-mesenchymal transitions in tumor progression. Nat. Rev. Cancer. 2:442–454.

    PubMed  Google Scholar 

  117. M. A. Perez-Moreno, A. Locascio, I. Rodrigo, G. Dhondt, F. Portillo, M. A. Nieto, and A. Cano (2001). A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J. Biol. Chem. 276(29):27424–27431.

    PubMed  Google Scholar 

  118. M. Schindl, S. F. Schoppmann, T. Strobel, H. Heinzl, C. Leisser, R. Horvat, and P. Birner (2003). Level of Id-1 protein expression correlates with poor differentiation, enhanced malignant potential, and more aggressive clinical behavior of epithelial ovarian tumors. Clin. Cancer. Res. 9(2):779–785.

    PubMed  Google Scholar 

  119. M. Schindl, G. Oberhuber, A. Obermair, S. F. Schoppmann, B. Karner, and P. Birner (2001). Overexpression of Id-1 protein is a marker for unfavorable prognosis in early-stage cervical cancer. Cancer Res. 61(15):5703–5706.

    PubMed  Google Scholar 

  120. N. Takai, T Miyazaki, K. Fujisawa, K. Nasu, and I. Miyakawa (2001). Id1 expression is associated with histological grade and invasive behavior in endometrial carcinoma. Cancer Lett. 165(2):185–193.

    PubMed  Google Scholar 

  121. M. A. Israel, M. C. Hernandez, M. Florio, P. J. Andres-Barquin, A. Mantani, J. H. Carter, and C. M. Julin (1999). Id gene expression as a key mediator of tumor cell biology. Cancer. Res. 59( 7 Suppl.):1726s-1730s.

    PubMed  Google Scholar 

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Desprez, PY., Sumida, T. & Coppé, JP. Helix-Loop-Helix Proteins in Mammary Gland Development and Breast Cancer. J Mammary Gland Biol Neoplasia 8, 225–239 (2003). https://doi.org/10.1023/A:1025957025773

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