Deregulated homeobox gene expression in cancer: Cause or consequence?

Nature Reviews Cancer

Volumn 2, Issue 10, 2002, Pages 777-785

  Abate Shen, Cory ^a  

^a RUTGERS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CANCER; CARCINOGENESIS; CELL DIFFERENTIATION; CELL GROWTH; GENE CLUSTER; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENE FUNCTION; HOMEOBOX; HUMAN; NONHUMAN; PRIORITY JOURNAL; REVIEW; TRANSCRIPTION REGULATION; ANIMAL; BIOLOGICAL MODEL; CHEMICAL STRUCTURE; DROSOPHILA; GENETICS; METABOLISM; NEOPLASM; PROTEIN TERTIARY STRUCTURE; PROTEIN TRANSPORT;

ANIMALS; DROSOPHILA; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENE EXPRESSION REGULATION, NEOPLASTIC; GENES, HOMEOBOX; HUMANS; MODELS, BIOLOGICAL; MODELS, MOLECULAR; NEOPLASMS; PROTEIN STRUCTURE, TERTIARY; PROTEIN TRANSPORT;

EID: 0036782277     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc907     Document Type: Review

References (102)

1. Duboule, D. (ed.) Guidebook to the Homeobox Genes (Oxford Univ. Press, New York, 1994).
2. Stein, S., Fritsch, R., Lemaire, L. & Kessel, M. Checklist: vertebrate homeobox genes. Mech. Dev. 55, 91-108 (1996).
3. Tupler, R., Penni, G. & Green, M. R. Expressing the human genome. Nature 409, 832-833 (2001).
4. Krumlauf, R. Hox genes in vertebrate development. Cell 78, 191-201 (1994).
5. Boncinelli, E., Mallamaci, A. & Lavorgna, G. Vertebrate homeobox genes. Genetica 94, 127-140 (1994).
6. Maconochie, M., Nonchev, S., Morrison, A. & Krumlauf, R. Paralogous Hox genes: function and regulation. Ann. Rev. Genet. 30, 529-556 (1996).
7. Duboule, D. Vertebrate Hox genes and proliferation: an alternative pathway to homeosis? Curr. Opin. Genet. Dev. 5, 525-528 (1995).
8. Chen, F. & Capecehi, M. R. Paralogous mouse Hox genes, Hoxa9, Hoxb9, and Hoxd9, function together to control development of the mammary gland in response to pregnancy. Proc. Natl Acad. Sci. USA 96, 541-546 (1999).
9. Davidson, D. The function and evolution of Msx genes: pointers and paradoxes. Trends Genet. 11, 405-411 (1995).
10. Bendall, A. J. & Abate-Shen, C. Roles for Msx and Dlx homeoproteins in vertebrate development. Gene 247, 17-31 (2000).
11. Song, K., Wang, Y. & Sassoon, D. Expression of Hox-7.1 in myoblasts inhibits terminal differentiation and induces cell transformation. Nature 360, 477-481 (1992). Shows that overpression of Msx1 (formerly Hox-7.1) in cell culture blocks differentiation and promotes a transformed phenotype.
12. Woloshin, P. et al. MSX1 inhibits myoD expression in fibroblast x 10T1/2 cell hybrids. Cell 82, 611-620 (1995).
13. Mina, M., Gluhak, J. & Rodgers, B. Downregulation of Msx-2 expression results in chondrogenesis in the medial region of the avian mandible. Connect. Tissue Res. 35, 79-84 (1996).
14. Dodig, M. et al. Ectopic Msx2 overexpression inhibits and Msx2 antisense stimulates calvarial osteoblast differentiation. Dev. Biol. 209, 298-307 (1999).
15. Hu, G., Lee, H., Price, S. M., Shen, M. M. & Abate-Shen, C. Msx homeobox genes inhibit differentiation through upregulation of cyclin D1. Development 128, 2373-2384 (2001). Proposes that inhibition of differentiation by Msx1 is a consequence of its ability to upregulate cyclin D1, which, in turn, prevents exit from the cell cycle.
16. Bhatia-Gaur, R. et al. Roles for Nkx3. 1 in prostate development and cancer. Genes Dev. 13, 966-977 (1999). Demonstrates that Nkx3.1-mutant mice are predisposed to prostate carcinoma; implicates the loss of function of this homeobox gene as a causal factor in prostate carcinogenesis.
17. Damante, G., Tell, G. & Di Lauro, R. A unique combination of transcription factors controls differentiation of thyroid cells. Prog. Nucleic Acid Res. Mol. Biol. 66, 307-356 (2001).
18. Harvey, R. P. NK-2 homeobox genes and heart development. Dev. Biol. 178, 203-216 (1996).
19. Maconochie, M. K. et al. Cross-regulation in the mouse HoxB complex: the expression of Hoxb2 in rhombomere 4 is regulated by Hoxb1. Genes Dev. 11, 1885-1895 (1997).
20. Ferretti, E. et al. Segmental expression of Hoxb2 in r4 requires two separate sites that integrate cooperative interactions between Prep1, Pbx and Hox proteins. Development 127, 155-166 (2000).
21. Livesey, F. J., Furukawa, T., Steffen, M. A., Church, G. M. & Cepko, C. L. Microarray analysis of the transcriptional network controlled by the photoreceptor homeobox gene Crx. Curr. Biol. 10, 301-310 (2000).
22. Mann, R. S. & Chan, S. K. Extra specificity from extradenticle: the partnership between HOX and PBX/EXD homeodomain proteins. Trends Genet. 12, 258-262 (1996).
23. Mann, R. S. & Affolter, M. Hox proteins meet more partners. Curr. Opin. Genet. Dev. 8, 423-429 (1998).
24. Rieckhof, G. E., Casares, F., Ryoo, H. D., Abu-Shaar, M. & Mann, R. S. Nuclear translocation of extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein. Cell 91, 171-183 (1997).
25. Abu-Shaar, M., Ryoo, H. D. & Mann, R. S. Control of the nuclear localization of Extradenticle by competing nuclear import and export signals. Genes Dev. 13, 935-945 (1999).
26. Biggin, M. D. & McGinnis, W. Regulation of segmentation and segmental identity by Drosophila homeoproteins: the role of DNA binding in functional activity and specificity. Development 124, 4425-4433 (1997).
27. Peverali, F. A. et al. Expression of HOX homeogenes in human neuroblastoma cell culture lines. Differentiation 45, 61-69 (1990).
28. Cillo, C. et al. HOX gene expression in normal and neoplastic human kidney. Int. J. Cancer 51, 892-897 (1992). One of the first studies to provide a comprehensive survey of Hox gene expression in cancer.
29. Cillo, C., Cantile, M., Faiella, A. & Boncinelli, E. Homeobox genes in normal and malignant cells. J. Cell. Physiol. 188, 161-169 (2001).
30. Kozmik, Z., Sure, U., Ruedi, D., Busslinger, M. & Aguzzi, A. Deregulated expression of PAX5 in medulloblastoma. Proc. Natl Acad. Sci. USA 92, 5709-5713 (1995).
31. Bowen, C. et al. Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res. 60, 6111-6115 (2000).
32. Ee, H. C., Erler, T., Bhathal, P. S., Young, G. P. & James, R. J. Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma. Am. J. Pathol. 147, 588-592 (1995).
33. Aberdam, D., Negreanu, V., Sachs, L. & Blatt, C. The oncogenic potential of an activated Hox-2.4 homeobox gene in mouse fibroblasts. Mol. Cell. Biol. 11, 554-557 (1991). One of the first papers to demonstrate the oncogenic potential of homeobox genes.
34. Maulbecker, C. C. & Gruss, P. The oncogenic potential of deregulated homeobox genes. Cell Growth Differ 4, 431-441 (1993). Shows that overexpression of several homeobox genes promote tumorigenesis. One of the first studies to suggest that the generality of deregulated homeobox genes indicate expression as a causal role in carcinoma.
35. Maulbecker, C. C. & Gruss, P. The oncogenic potential of Pax genes. EMBO J. 12, 2361-2367 (1993).
36. Takahashi, C. et al. Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene. Oncogene 12, 2137-2146 (1996).
37. Takahashi, C., Akiyama, N., Kitayama, H., Takai, S. & Noda, M. Possible involvement of MSX-2 homeoprotein in v-ras-induced transformation. Leukemia 11, 340-343 (1997).
38. Care, A. et al. HOXB7 constitutively activates basic fibroblast growth factor in melanomas. Mol. Cell. Biol. 16, 4842-4851 (1996).
39. Naora, H. et al. A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells. Proc. Natl Acad. Sci. USA 98, 4060-4065 (2001).
40. Hall, M. & Peters, G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. 68, 67-108 (1996).
41. Suzuki, M. et al. Over-expression of HOX-8, the human homologue of the mouse Hox-8 homeobox gene, in human tumors. Biochem. Biophys. Res. Commun 194, 187-193 (1993).
42. Ford, H. L., Kabingu, E. N., Bump, E. A., Mutter, G. L. & Pardee, A. B. Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis. Proc. Natl Acad. Sci. USA 95, 12608-12613 (1998). Demonstrates that overexpression of HSIX1 promotes tumorigenesis by abrogating the G2 cell-cycle checkpoint.
43. Ford, H. L. et al. Cell cycle-regulated phosphorylation of the human SIX1 homeodomain protein. J. Biol. Chem. 275, 22245-22254 (2000).
44. Kawabe, T., Muslin, A. J. & Korsmeyer, S. J. HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint. Nature 385, 454-458 (1997). Proposes that the oncogenic potential of HOX11 is mediated by altering the cell cycle, which is a consequence of its interaction with protein phosphatases that regulate the G2/M cell-cycle checkpoint. One of the first examples showing that homeobox genes can promote oncogenesis by perturbing cell-cycle control.
45. Hatano, M., Roberts, C. W., Minden, M., Crist, W. M. & Korsmeyer, S. J. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukaemia Science 253, 79-82 (1991).
46. Kennedy, M. A. et al. HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24. Proc. Natl Acad. Sci. USA 88. 8900-8904 (1991).
47. Dube, I. D. et al. A novel human homeobox gene lies at the chromosome 10 breakpoint in lymphoid neoplasias with chromosomal translocation t(10;14). Blood 78, 2996-3003 (1991).
48. Lu, M., Gong, Z. Y., Shen, W. F. & Ho, A. D. The tcl-3 proto-oncogene altered by chromosomal translocation in T-cell leukaemia codes for a homeobox protein. EMBO J. 10, 2905-2910 (1991).
49. Dear, T. N. et al. The Hox11 gene is essential for cell survival during spleen development. Development 121, 2909-2915 (1995).
50. Raman, V. et al. Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature 405, 974-978 (2000).
51. Smith, R. C. et al. p21CIP1-mediated inhibition of cell proliferation by overexpression of the gax homeodomain gene. Genes Dev. 11, 1674-1689 (1997). Shows that overexpression of GAX leads to upregulation of WAF1, which, in turn, leads to cell-cycle arrest.
52. James, R. & Kazenwadel, J. Homeobox gene expression in the intestinal epithelium of adult mice. J. Biol. Chem. 266, 3246-3251 (1991).
53. James, R., Erler, T. & Kazenwadel, J. Structure of the murine homeobox gene cdx-2. Expression in embryonic and adult intestinal epithelium. J. Biol. Chem. 269, 15229-15237 (1994).
54. Silberg, D. G., Swain, G. P., Suh, E. R. & Traber, P. G. Cdx1 and cdx2 expression during intestinal development. Gastroenterology 119, 961-971 (2000).
55. Mallo, G. V. et al. Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis. Int. J. Cancer 74, 35-44 (1997).
56. Hinoi, T. et al. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am. J. Pathol. 159, 2239-2248 (2001).
57. Chawengsaksophak, K., James, R., Hammond, V. E., Kontgen, F. & Beck, F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature 386, 84-87 (1997). Demonstrates that Cdx2 heterozygous mutant mice develop precancerous lesions of the intestine that are coincident with loss of Cdx2 protein expression. One of the first studies to associate loss (rather than gain) of function of a homeobox gene with carcinogenesis.
58. Mallo, G. V. et al. Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells. J. Biol. Chem. 273, 14030-14036 (1998).
59. Suh, E. & Traber, P. G. An intestine-specific homeobox gene regulates proliferation and differentiation. Mol. Cell. Biol. 16, 619-625 (1996).
60. Tamai, Y. et al. Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice. Cancer Res. 59, 2965-2970 (1999).
61. Sivagnanasundaram, S. et al. The homeobox gene CDX2 in colorectal carcinoma: a genetic analysis. Br. J. Cancer 84, 218-25 (2001).
62. Wicking, C. et al. CDX2, a human homologue of Drosophila caudal, is mutated in both alleles in a replication error positive colorectal cancer. Oncogene 17, 657-659 (1998).
63. Biebench, C. J., Fujita, K., He, W. W. & Jay, G. Prostate-specific and androgen-dependent expression of a novel homeobox gene. J. Biol. Chem. 271, 31779-31782 (1996).
64. He, W. W. et al. A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics 43, 69-77 (1997).
65. Prescott, J. L., Blok, L. & Tindall, D. J. Isolation and androgen regulation of the human homeobox cDNA, NKX3.1. Prostate 35, 71-80 (1998).
66. Sciavolino, P. J. & Abate-Shen, C. Molecular biology of prostate development and prostate cancer. Ann. Med. 30, 357-368 (1998).
67. Tanaka, M. et al. Nkx3.1, a murine homolog of Drosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Dev. Dyn. 219, 248-260 (2000).
68. Kim, M. J. et al. Nkx3.1 mutant mice recapitulate early stages of prostate carcinogenesis. Cancer Res. 62, 2999-3004 (2002).
69. Abdulkadir, S. A. et al. Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. Mol. Cell. Biol. 22, 1495-1503 (2002).
70. Kim, M. J. et al. Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc. Natl Acad. Sci. USA 99, 2884-2889 (2002).
71. Voeller H. J. et al. Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers. Cancer Res. 57, 4455-4459 (1997).
72. Vocke, C. D. et al. Analysis of 99 microdissected prostate carcinomas reveals a high frequency of allelic loss on chromosome 8p12-21. Cancer Res. 56, 2411-2416 (1996).
73. Emmert-Buck, M. R. et al. Allelic loss on chromosome 8p12-21 in microdissected prostati intraepithelial neoplasia. Cancer Res. 55, 2959-2962 (1995).
74. Lawrence, H. J., Sauvageau, G., Humphries, R. K. & Largman, C. The role of HOX homeobox genes in normal and leukemic hematopoiesis. Stem Cells 14, 281-291 (1996).
75. Look, A. T. Oncogenic transcription factors in the human acute leukemias. Science 278, 1059-1064 (1997)
76. van Oostveen, J., Bijl, J., Raaphorst, F., Walboomers, J. & Meijer, C. The role of homeobox genes in normal hematopoiesis and hematological malignancies. Leukemia 13, 1675-1690 (1999).
77. Quon, K. C. & Berns, A. Haplo-insufficiency? Let me count the ways. Genes Dev. 15, 2917-2921 (2001).
78. Barr, F. G. The role of chimeric paired box transcription factors in the pathogenesis of paediatric rhabdomysarcoma. Cancer Res. 59, 1711s-1715s (1999).
79. Barr, F. G. et al. Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nature Genet. 3, 113-117 (1993).
80. Davis, R. J., D'Cruz, C. M., Lovell, M. A., Biegel, J. A. & Barr, F. G. Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res. 54, 2869-2872 (1994).
81. Lam, P. Y., Sublett, J. E., Hollenbach, A. D. & Roussel, M. F. The oncogenic potential of the Pax3-FKHR fusion protein requires the Pax3 homeodomain recognition helix but not the Pax3 paired-box DNA binding domain. Mol. Cell. Biol. 19, 594-601 (1999).
82. Kamps, M. P. & Baltimore, D. E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukaemia, causes acute myeloid leukaemia in mice. Mol. Cell. Biol. 13, 351-357 (1993).
83. Nourse, J. et al. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60, 535-545 (1990).
84. Borrow, J. et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nature Genet. 12, 159-167 (1996).
85. Nakamura, T. et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nature Genet. 12, 154-158 (1996).
86. Calvo, K. R., Sykes, D. B., Pasillas, M. P. & Kamps, M. P. Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1. Oncogene 21, 4247-4256 (2002).
87. Nakamura, T., Yamazaki, Y., Hatano, Y. & Miura, I. NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukaemia with chromosome translocation t(1;11)(q23;p15). Blood 94, 741-747 (1999).
88. Dubrulle, J., McGrew, M. J. & Pourquie, O. FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell 106, 219-232 (2001).
89. Zakany, J., Kmita, M., Alarcon, P., de la Pompa, J. L. & Duboule, D. Localized and transient transcription of Hox genes suggests a link between patterning and the segmentation clock. Cell 106, 207-217 (2001).
90. Boyl, P. P. et al. Forebrain and midbrain development requires epiblast-restricted Otx2 translational control mediated by its 3′ UTR. Development 128, 2989-3000 (2001).
91. Friedmann, Y., Daniel, C. A., Strickland, P. & Daniel, C. W. Hox genes in normal and neoplastic mouse mammary gland. Cancer Res. 54, 5981-5985 (1994).
92. De Vita, G. et al. Expression of homeobox-containing genes in primary and metastatic colorectal cancer. Eur. J. Cancer 6, 887-893 (1993).
93. Tibedo, C. et al. HOX gene expression in human small-cell lung cancers xenografted into nude mice. Int. J. Cancer 58, 608-615 (1994).
94. Li, C. M. et al. Gene expression in Wilms' tumor mimics the earliest committed stage in the metanephric mesenchymal-epithelial transition. Am. J. Pathol. 160, 2181-2190 (2002).
95. Gao, A. C. & Isaacs, J. T. Expression of homeobox gene-GBX2 in human prostatic cancer cells. Prostate 29, 395-398 (1996).
96. Gao, A. C., Lou, W. & Isaacs, J. T. Down-regulation of homeobox gene GBX2 expression inhibits human prostate cancer clonogenic ability and tumorigenicity. Cancer Res. 58, 1391-1394 (1998).
97. Gao, A. C., Lou, W. & Isaacs, J. T. Enhanced GBX2 expression stimulates growth of human prostate cancer cells via transcriptional up-regulation of the interleukin 6 gene. Clin. Cancer Res. 6, 493-497 (2000).
98. Dressler, G. R. & Douglass, E. C. Pax-2 is a DNA-binding protein expressed in embryonic kidney and Wilms tumor. Proc. Natl Acad. Sci. USA 89, 1179-1183 (1992).
99. Poleev, A. et al. PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. Development 116, 611-623 (1992).
100. Silberstein, G. B., Dressler, G. R. & Van Horn, K. Expression of the PAX2 oncogene in human breast cancer and its role in progesterone-dependent mammary growth. Oncogene 21, 1009-1016 (2002).
101. Kroll, T. G. et al. PAX8-PPARγ1 fusion oncogene in human thyroid carcinoma. Science 289, 1357-1360 (2000).
102. Sellar, G. C. et al. BARX2 induces cadherin 6 expression and is a functional suppressor of ovarian cancer progression. Cancer Res. 61, 6977-6981 (2001).