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Tumor suppressor genes and their roles in breast cancer

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Summary

Tumor suppressor genes have been identified by the occurrence of mutations in many families with hereditary forms of cancer, exposed during development of the tumor by loss of heterozygosity. They have a number of diverse functions. For example, both theRB gene of retinoblastoma and thep53 gene, which is commonly mutated in breast and colon cancer among others, produce proteins involved in distinct steps of cell cycle control, while thenm23 product prevents metastasis. Here we review the data developed until now on the possible presence and role of mutations in these and other tumor suppressor genes in breast cancer. A more complete understanding of the tumor suppressor genes could not only provide diagnostic information, but could lead to specific gene therapy to replace suppressor functions lost in individual tumors.

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References

  1. Knudson AG: Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823, 1971

    Google Scholar 

  2. Lynch H: Hereditary breast cancer. Ann Med 23: 475–477, 1991

    Google Scholar 

  3. Foulds L: The natural history of cancer. J Chronic Dis 8:2–37, 1958

    Google Scholar 

  4. Knudson AJ: Pediatric molecular oncology. Past as prologue to the future. Cancer 71 (10 Suppl):3320–3324, 1993

    Google Scholar 

  5. Klein G: Genes that can antagonize tumor development. FASEB J 7(10):821–825, 1993

    Google Scholar 

  6. Goodrich DW, Lee W-H: Molecular characterization of the retinoblastoma susceptibility gene. Biochim Biophys Acta 1155:43–61, 1993

    Google Scholar 

  7. Vogel F: Genetics of retinoblastoma. Hum Genet 52:1–54, 1979

    Google Scholar 

  8. Cavenee WK et al: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779–784, 1983

    Google Scholar 

  9. Dryja TP et al: Molecular detection of deletions involving band q14 chromosome 13 in retinoblastomas. Proc Natl Acad Sci USA 83:7391–7394, 1986

    Google Scholar 

  10. Friend SH et al: A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature (London) 323:643–646, 1986

    Google Scholar 

  11. Fung YKT et al: Structural evidence for the authenticity of the human retinoblastoma gene. Science 236:1657–1661, 1987

    Google Scholar 

  12. Lee W-H et al: Human retinoblastoma susceptibility gene: Cloning, identification, and sequence. Science 235:1394–1399, 1987

    Google Scholar 

  13. Francke U: Retinoblastoma and chromosome 13. Birth Defects 12:131–137, 1976

    Google Scholar 

  14. Yunis JJ, Ramsay N: Retinoblastoma and subband deletion of chromosome 13. Am J Dis Child 132: 161–163, 1978

    Google Scholar 

  15. Dunn JM et al: Mutations in the RB1 gene and their effects on transcription. Mol Cell Biol 9:4596–4604, 1989

    Google Scholar 

  16. Lee E-H: Tumor suppressor genes: A new era for molecular genetic studies of cancer. Breast Cancer Res Treat 19:3–13, 1991

    Google Scholar 

  17. Friend SH et al: Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: Organization of the sequence and its encoded protein. Proc Natl Acad Sci USA 84:9059–9063, 1987

    Google Scholar 

  18. Shew J-Y et al: Antibodies detecting abnormalities of the retinoblastoma susceptibility gene product (pp110RB) in osteosarcomas and synovial sarcomas. Oncogene Res 1:205–214, 1989

    Google Scholar 

  19. Szekely L et al: Cell type and differentiation dependent heterogeneity in retinoblastoma protein expression in SCID mouse fetuses. Cell Growth Differ 3:139–156, 1992

    Google Scholar 

  20. Hong FD et al: Structure of the human retinoblastoma gene. Proc Natl Acad Sci USA 86:5502–5506, 1989

    Google Scholar 

  21. Buchkovich K, Duffy LA, Harlow: The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 58:1097–1105, 1989

    Google Scholar 

  22. Chen L-C, Dollbaum C, Smith HS: Loss of heterozygosity on chromosome lq in human breast cancer. Proc Natl Acad Sci USA 86:7204–7207, 1989

    Google Scholar 

  23. Ludlow JW et al: The retinoblastoma susceptibility gene product undergoes cell cycle-dependent dephosphorylation and binding to and release from SV40 large T. Cell 60:387–396, 1990

    Google Scholar 

  24. Mihara K et al: Cell cycle-dependent regulation of phosphorylation of the human retinoblastoma gene product. Science 246:1300–1303, 1989

    Google Scholar 

  25. Xu H-J et al: The retinoblastoma susceptibility gene product: A characteristic pattern in normal cells and abnormal expression in malignant cells. Oncogene 4:807–812, 1989

    Google Scholar 

  26. Lees JA et al: The retinoblastoma protein is phosphorylated on multiple sites by human cec2. EMBO J 10:4279–4289, 1991

    Google Scholar 

  27. Lin BT-Y et al: Retinoblastoma cancer suppressor gene product is a substrate of the cell cycle regulator cdc2 kinase. EMBO J 10:857–864, 1991

    Google Scholar 

  28. Goodrich DW et al: The retinoblastoma gene product regulates progression through G1 phase of the cell cycle. Cell 67:293–302, 1991

    Google Scholar 

  29. Hinds PW et al: Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 70:993–1006, 1992

    Google Scholar 

  30. Qin X-Q et al: Identification of a growth suppression domain within the retinoblastoma gene product. Genes Devel 6:953–964, 1992

    Google Scholar 

  31. Clarke AR et al: Requirement for a functional Rb-1 gene in murine development. Nature 359:328–330, 1992

    Google Scholar 

  32. Jacks T et al: Effects of an Rb mutation in the mouse. Nature 359:294–300, 1992

    Google Scholar 

  33. Lee EY et al: Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359:288–294, 1992

    Google Scholar 

  34. Hu N et al: Heterozygous Rb-1/+ mice are predisposed to tumors of the pituitary glands with a nearly complete penetrance. Oncogene 9:1021–1027, 1994

    Google Scholar 

  35. Huang H-JS et al: Suppression of the neoplastic phenotype by replacement of the retinoblastoma gene product in human cancer cells. Science 242:1563–1566, 1988

    Google Scholar 

  36. Madreperla SA et al: Intraocular tumor suppression of retinoblastoma gene-reconstituted retinoblastoma cells. Cancer Res 51:6381–6384, 1991

    Google Scholar 

  37. Muncaster MM et al: Failure of RB1 to reverse the malignant phenotype of human tumor cell lines. Cancer Res 52:654–661, 1992

    Google Scholar 

  38. Chen PL et al: Stability of RB expression determines the tumorigenicity of reconstituted retinoblastoma cells. Cell Growth Differ 3:119–125, 1992

    Google Scholar 

  39. Sumegi J, Uzvolgyi E, Klein G: Expression of the RB gene under the control of MuLV-LTR suppresses tumorigenicity of WERI-Rb-27 retinoblastoma cells in immunodefective mice. Cell Growth Differ 1:247–250, 1990

    Google Scholar 

  40. Abramson DH et al: Second nonocular tumors in retinoblastoma survivors. Ophthalmology 91:1351–1355, 1984

    Google Scholar 

  41. Bookstein R et al: Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 247:712–715, 1990

    Google Scholar 

  42. Goodrich DW, Chen Y-M, Scully P, Lee W-H: Expression of the retinoblastoma gene product suppresses the tumorigenicity of bladder carcinoma cells. Cancer Res 52:1968–1973, 1992

    Google Scholar 

  43. Wang NP et al: Tumor suppressor activity of RB and p53 genes in human breast carcinoma cells. Oncogene 8:279–288, 1993

    Google Scholar 

  44. Lee W-H et al: The retinoblastoma susceptibility gene product is a nuclear phosphoprotein associated with DNA binding activity. Nature 329:642–645, 1987

    Google Scholar 

  45. Whyte P, Williamson NM, Harlow E: Cellular targets for transformation by the adenovirus E1A proteins. Cell 56:67–75, 1989

    Google Scholar 

  46. DeCaprio JA et al: SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54:275–283, 1988

    Google Scholar 

  47. Dyson N et al: The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937, 1989

    Google Scholar 

  48. Kim S-J et al: Retinoblastoma gene product activates expression of the human TGF-β2 gene through transcription factor ATF-2. Nature 358:331–334, 1992

    Google Scholar 

  49. Rustgi AK, Dyson N, Bernards R: Amino-terminal domains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product. Nature 352:541–544, 1991

    Google Scholar 

  50. Kaelin WGJ et al: Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. Cell 64:521–532, 1991

    Google Scholar 

  51. Lee W-H et al: RB protein as a cellular ‘corral’ for growth-promoting proteins. Cold Spring Harbor Symp Quant Biol 56:211–217, 1991

    Google Scholar 

  52. Qian Y-W et al: A retinoblastoma-binding protein related to a negative regulator of Ras in yeast. Nature 364:648–652, 1993

    Google Scholar 

  53. DeFeo-Jones D et al: Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product. Nature 352:251–254, 1991

    Google Scholar 

  54. Helin K et al: A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F. Cell 70:337–350, 1992

    Google Scholar 

  55. Shan B et al: Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: Identification of a gene with properties of the transcription factor E2F. Mol Cell Biol 12:5620–5631, 1992

    Google Scholar 

  56. Durfee T et al: The retinoblastoma protein associates with the protein phosphatase type I catalytic subunit. Genes Devel 7:555–569, 1993

    Google Scholar 

  57. Kovesdi I, Reichel R, Nevins JR: Identification of a cellular transcription factor involved in E1A transactivation. Cell 45:219–228, 1986

    Google Scholar 

  58. Nevin JR: A link between the Rb tumor suppressor protein and viral oncoproteins. Science 258:424–429, 1992

    Google Scholar 

  59. Johnson D et al: Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 365:349–352, 1993

    Google Scholar 

  60. Hamel PA et al: Transcriptional repression of the E2-containing promoters EIIaE, c-myc, and RB1 gene. Mol Cell Biol 12:3431–3438, 1992

    Google Scholar 

  61. Lee EY-HP et al: Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 241:218–221, 1988

    Google Scholar 

  62. Tang A et al: Structural rearrangement of the retinoblastoma gene in human breast carcinoma. Science 242:263–266, 1988

    Google Scholar 

  63. Devilee P et al: Frequent somatic imbalance of marker alleles for chromosome 1 in human primary breast carcinoma. Cancer Res 51:1020–1025, 1991

    Google Scholar 

  64. Andersen TI et al: Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. Genes Chromosomes Cancer 4:113–121, 1992

    Google Scholar 

  65. Borg A et al: The retinoblastoma gene in breast cancer: Allele loss is not correlated with loss of gene protein expression. Cancer Res 52:2991–2994, 1992

    Google Scholar 

  66. Spandidos D et al: Expression of Ras Rb1 and p53 in human breast cancer. Anticancer Res 12:81–90, 1992

    Google Scholar 

  67. Trudel M et al: Retinoblastoma and p53 gene product expression in breast carcinoma: Immunohistochemical analysis and clinicopathologic correlation. Human Pathol 23:1388–1394, 1992

    Google Scholar 

  68. Varley JM et al: The retinoblastoma gene is frequently altered leading to loss of expression in primary breast tumours. Oncogene 4:725–729, 1989

    Google Scholar 

  69. Ewen ME et al: Molecular cloning, chromosome mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein. Cell 66:1155–1164, 1991

    Google Scholar 

  70. Mayol X et al: Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogene 8:2561–2566, 1993

    Google Scholar 

  71. Li Y et al: The adenovirus E1A-associated 130 kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Devel 7:2366–2377, 1993

    Google Scholar 

  72. Cobrinik D et al: Cell cycle-specific association of E2F with the p130 E1A-binding protein. Genes Develop 7:2392–2404, 1993

    Google Scholar 

  73. Hannon G, Demetrick D, Beach D: Isolation of the Rbrelated p130 through its interaction with CDK2 and cyclins. Genes Devel 7:2378–2391, 1993

    Google Scholar 

  74. Dutrillaux B, Gerbault-Seureau M, Zafrani B: Characterization of chromosomal anomalies in human breast cancer. Cancer Genet Cytogenet 49:203–217, 1990

    Google Scholar 

  75. Lane DP, Crawford LV: T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263, 1979

    Google Scholar 

  76. Eliyahu D et al: Participation of p53 cellular tumour antigen in transformation of normal embryonic fibroblasts. Nature 312:646–649, 1984

    Google Scholar 

  77. Hinds PW, Finlay CA, Levine AJ: Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J Virol 63:739–746, 1989

    Google Scholar 

  78. Baker SJ et al: Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249: 912–915, 1990

    Google Scholar 

  79. Hollstein M et al: p53 mutations in human cancers. Science 253:49–53, 1991

    Google Scholar 

  80. Malkin D et al: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238, 1990

    Google Scholar 

  81. Srivastava S et al: Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348:747–749, 1990

    Google Scholar 

  82. Li FP, Fraumeni JF: Soft-tissue sarcomas, breast cancer, and other neoplasms, a familial syndrome? Ann Intern Med 71:747–751, 1969

    Google Scholar 

  83. Chen P-L et al: Genetic mechanisms of tumor suppression by the human p53 gene. Science 251:1576–1580, 1990

    Google Scholar 

  84. Farmer GJ et al: Wild-type p53 activates transcriptionin vitro. Nature 358:83, 1992

    Google Scholar 

  85. Fields S, Jang SK: Presence of a potent transcription activating sequence in the p53 protein. Science 249:1046–1051, 1990

    Google Scholar 

  86. El-Deiry WS et al: Definition of a consensus binding site for p53. Nature Genet 1:45, 1992

    Google Scholar 

  87. Funk WD et al: A transcriptionally active DNA-binding site for human p53 protein complexes. Mol Cell Biol 12:2866–2871, 1992

    Google Scholar 

  88. Fakharzadeh SS, Trusko SP, George DL: Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J 10:1565–1569, 1991

    Google Scholar 

  89. Momand J et al: The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245, 1992

    Google Scholar 

  90. El-Deiry WS et al: WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825, 1993

    Google Scholar 

  91. Harper JW et al: The p21 CDK-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805–816, 1993

    Google Scholar 

  92. Kastan MB et al: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51:6304–6311, 1991

    Google Scholar 

  93. Kuerbitz SJ et al: Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89:7491–7495, 1992

    Google Scholar 

  94. Kastan MB et al: A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71:587–597, 1992

    Google Scholar 

  95. Lane DP: p53, guardian of the genome. Nature 358:15–16, 1992

    Google Scholar 

  96. Clarke AR et al: Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362:849–852, 1993

    Google Scholar 

  97. Lowe SW et al: p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362:849, 1993

    Google Scholar 

  98. Kastan MB: p53: Evolutionally conserved and constantly evolving. J NIH Res 5:53–57, 1993

    Google Scholar 

  99. Zambetti G, Levine A: A comparison of the biological activities of wild-type and mutant p53. FASEB J 7:855–865, 1993

    Google Scholar 

  100. Lavigueur A et al: High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9:3892–3991, 1989

    Google Scholar 

  101. Lozano G, Levine AJ: Tissue-specific expression of p53 in transgenic mice is regulated by intron sequences. Mol Carcinogen 4:3–9, 1991

    Google Scholar 

  102. Donehower LA: Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221, 1992

    Google Scholar 

  103. Harvey M et al: In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8:2457–2467, 1991

    Google Scholar 

  104. Casey G et al: Growth suppression of human breast cancer cells by the introduction of a wild-type p53 gene. Oncogene 6:1791–1797, 1991

    Google Scholar 

  105. Gessler M et al: Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343:774–778, 1990

    Google Scholar 

  106. Call KM et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60:509–520, 1990

    Google Scholar 

  107. Yeger H et al: Coordinate expression of Wilms' tumor genes correlated with Wilms' tumor phenotypes. Cell Growth & Differentiation 3:855–864, 1992

    Google Scholar 

  108. Dowdy S et al: Suppression of tumorigenicity in Wilms tumor by the p15.5-p14 region of chromosome 11. Science 254:293–295, 1991

    Google Scholar 

  109. Coppes MJ, Campbell CE, Williams BRG: The role of WT1 in Wilms tumorigenesis. FASEB J 7:886–895, 1993

    Google Scholar 

  110. Kreidberg JA et al: WT-1 is required for early kidney development. Cell 74:679–691, 1993

    Google Scholar 

  111. Cawthon RM et al: A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 63:193–201, 1990

    Google Scholar 

  112. Viskochil D et al: Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62:187–192, 1990

    Google Scholar 

  113. Wallace MR et al: Type 1 neurofibromatosis gene: Identification of a large transcript disrupted in three NF1 patients. Science 249:181–186, 1990

    Google Scholar 

  114. Gutmann D, Wood D, Collins F: Identification of the neurofibromatosis type 1 gene product. Proc Natl Acad Sci USA 88:9658–9662, 1991

    Google Scholar 

  115. Nishi T et al: Differential expression of two types of the neurofibromatosis type 1 (NF1) gene transcripts related to neuronal differentiation. Oncogene 6:1555–1559, 1991

    Google Scholar 

  116. Suzuki Y et al: Brain tumors predominantly express the neurofibromatosis type 1 gene transcripts containing the 63-base insert in the region coding for GTP-ase activating protein related domain. Biochem Biophys Res Commun 181:955–961, 1991

    Google Scholar 

  117. Xu G et al: The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608, 1990

    Google Scholar 

  118. Ballester R et al: The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63:851–859, 1990

    Google Scholar 

  119. Martin GA et al: The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63:843–849, 1990

    Google Scholar 

  120. Xu G et al: The catalytic domain of the neurofibromatosis type 1 gene product stimulatesras GTPase and complementsira mutants ofS. cerevisiae. Cell 63:835–841, 1990

    Google Scholar 

  121. McCormick F et al: Regulation of ras p21 by GTP-ase activating proteins. Cold Spring Harbor Symp Quant Biol 56:237–241, 1991

    Google Scholar 

  122. Bourne H, Sanders D, McCormick F: The GTPase superfamily: A conserved switch for diverse cell functions. Nature 348:125–132, 1990

    Google Scholar 

  123. Marshall M, Hettich L: Characterization of ras effector mutant interactions with the NF1-GAP related domain. Oncogene 8:425–431, 1993

    Google Scholar 

  124. Legius E et al: Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumor suppressor gene hypothesis. Nat Genet 3:122–126, 1993

    Google Scholar 

  125. Li Y et al: Somatic mutations in the neurofibromatosis 1 gene in human cancers. Cell 69:275–281, 1992

    Google Scholar 

  126. Ali IU et al: Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia. Science 238:185–188, 1987

    Google Scholar 

  127. Rouleau GA et al: Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature 363:515–521, 1993

    Google Scholar 

  128. Trofatter J et al: A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791–800, 1993

    Google Scholar 

  129. Martuza R, Eldridge R: Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318:684–688, 1988

    Google Scholar 

  130. Krieg J, Hunter T: Identification of the two major epidermal growth factor-induced tyrosine phosphorylation sites in the microvillar core protein ezrin. J Biol Chem 267:19258–19265, 1992

    Google Scholar 

  131. Fazioli F et al: The ezrin-like family of tyrosine kinase substrates: Receptor-specific pattern of tyrosine phosphorylation and relationship to malignant transformation. Oncogene 8:1335–1345, 1993

    Google Scholar 

  132. Larsson C et al: Genomic alterations in human breast carcinomas. Genes Chrom Cancer 2:191–197, 1990

    Google Scholar 

  133. Maher E et al: Von Hippel-Lindau disease: A genetic study. J Med Genet 28:443–447, 1991

    Google Scholar 

  134. Latif F et al: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320, 1993

    Google Scholar 

  135. Groden J et al: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600, 1991

    Google Scholar 

  136. Kinzler KW: Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251:1366–1370, 1991.

    Google Scholar 

  137. Nishisho I et al: Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–559, 1991

    Google Scholar 

  138. Powell SM et al: APC mutations occur early during colorectal tumorigenesis. Nature 359:235–237, 1992

    Google Scholar 

  139. Ichii S et al: Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). Hum Mol Genet 1:387–390, 1992

    Google Scholar 

  140. Smith K et al: The APC gene product in normal and tumor cells. Proc Natl Acad Sci USA 90:2846–2850, 1993

    Google Scholar 

  141. Bourne HR: Colon cancer. Consider the coiled coil. Nature 351:188–190, 1991

    Google Scholar 

  142. Su LK et al: Association between wild type and mutant APC gene products. Cancer Res 53:2728–2731, 1993

    Google Scholar 

  143. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61:759–767, 1990

    Google Scholar 

  144. D'Amico D et al: Polymorphic sites within the MCC and APC loci reveal very frequent loss of heterozygosity in human small cell lung cancer. Cancer Res 52:1996–1999, 1992

    Google Scholar 

  145. Boynton R et al: Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. Proc Natl Acad Sci USA 89:3385–3388, 1992

    Google Scholar 

  146. Nakatsuru S et al: Somatic mutation of the APC gene in gastric cancer: Frequent mutations in very well differentiated adenocarcinomas and signet-ring cell carcinoma. Hum Mol Genet 1:559–563, 1992

    Google Scholar 

  147. Horii A et al: The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer. Cancer Res 52:3231–3233, 1992

    Google Scholar 

  148. Thompson AM et al: Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer. Br J Cancer 68:64–68, 1993

    Google Scholar 

  149. Aaltonen LA et al: Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816, 1993

    Google Scholar 

  150. Fishel R et al: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038, 1993

    Google Scholar 

  151. Steeg P et al: Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80:200–204, 1988

    Google Scholar 

  152. Caligo M et al: Decreasing expression of nm23 gene in metastatic murine mammary tumors of viral etiology (MMTV). Anticancer Res 12:969–974, 1992

    Google Scholar 

  153. Su Z et al: Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-rastransformed cloned rat embryo fibroblast cells. Oncogene 8:1211–1219, 1993

    Google Scholar 

  154. Bevilacqua G et al: Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential. Cancer Res 49:5185–5190, 1989

    Google Scholar 

  155. Hennessy C et al: Expression of the antimetastatic gene nm23 in human breast cancer: An association with good prognosis. J Natl Cancer Inst 83:281–285, 1991

    Google Scholar 

  156. Leone A et al: Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65:25–35, 1991

    Google Scholar 

  157. Leone A et al: Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: Effects on tumor metastatic potential, colonization and enzymatic activity. Oncogene 8:2325–2333, 1993

    Google Scholar 

  158. Gilles A et al: Nucleoside diphosphate kinase from human erythrocytes. J Biol Chem 266:8784–8789, 1991

    Google Scholar 

  159. MacDonald NJ et al: A serine phosphorylation of Nm23, and not its nucleoside diphosphate kinase activity, correlates with suppression of tumor metastatic potential. J Biol Chem 268:25780–25789, 1993

    Google Scholar 

  160. Kantor J et al: Inhibition of cell motility after nm23 transfection of human and murine tumor cells. Cancer Res 53:1971–1973, 1993

    Google Scholar 

  161. Postel E et al: Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261:478–480, 1993

    Google Scholar 

  162. Cavenee WK et al: Genetic origin of mutations predisposing to retinoblastoma. Science 288:501–503, 1985

    Google Scholar 

  163. Hall JM et al: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–1689, 1990

    Google Scholar 

  164. Narod SA et al: Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338:82–83, 1991

    Google Scholar 

  165. Hall J et al: Closing in on a breast cancer gene on chromosome 17q. Am J Hum Gen 50:1235–1242, 1992

    Google Scholar 

  166. Easton DF et al: Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families. Am J Hum Gen 52:678–701, 1993

    Google Scholar 

  167. Smith SA et al: Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wildtype chromosome. Nature Genetics 2:128–131, 1992

    Google Scholar 

  168. Eccles D et al: Allele loss on chromosome 17 in human epithelial ovarian carcinoma. Oncogene 5:1599–1601, 1990

    Google Scholar 

  169. Sato T et al: Allelotype of human ovarian cancer. Cancer Res 51:5118–5122, 1992

    Google Scholar 

  170. Saito H et al: Detailed deletion mapping of chromosome 17q in ovarian and breast cancer: 2 cM region on 17q21.3 often and commonly deleted in tumors. Cancer Res 53:3382–3385, 1993

    Google Scholar 

  171. Emi M et al: A novel metalloprotease/disintegrin-like gene at 17q12.3 is somatically rearranged in two primary breast cancers. Nature Genetics 5:151–157, 1993

    Google Scholar 

  172. Horowitz JM et al: Point mutational inactivation of the retinoblastoma antioncogene. Science 243:937–940, 1989

    Google Scholar 

  173. Miller A: Human gene therapy comes of age. Nature 357:455–460, 1992

    Google Scholar 

  174. Mulligan R: The basic science of gene therapy. Science 260:926–932, 1993

    Google Scholar 

  175. Miller A: Retrovirus packaging cells. Human Gene Ther 1:5–14, 1990

    Google Scholar 

  176. Ohashi T et al: Efficient transfer and sustained high expression of the human glucocerebrosidase gene in mice and their functional macrophages following transplantation of bone marrow transduced by a retroviral vector. Proc Natl Acad Sci USA 89:11332–11336, 1992

    Google Scholar 

  177. Rosenberg S: Immuno-therapy and gene therapy of cancer. Cancer Res 51:5074–5079, 1991

    Google Scholar 

  178. Rosenfeld M et al: In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68:143–155, 1992

    Google Scholar 

  179. Quantin B et al: Adenovirus as an expression vector in muscle cell in vivo. Proc Natl Acad Sci USA 89:2581–2584, 1992

    Google Scholar 

  180. Wagner E et al: Coupling of adenovirus to transferrin-polylysine/DNA complexes greatly enhances receptor-mediated gene delivery and expression of transfected genes. Proc Natl Acad Sci USA 89:6099–6103, 1992

    Google Scholar 

  181. Wagner E et al: Influenza virus hemagglutinin HA-2 N-terminal fusogenic peptides augment gene transfer by transferrin-polylysine-DNA complexes: Toward a synthetic virus-like gene-transfer vehicle. Proc Natl Acad Sci USA 89:7934–7938, 1992

    Google Scholar 

  182. Alton E et al: Non-invasive liposome-mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice. Nature Genet 5:135–142, 1993

    Google Scholar 

  183. Hyde S et al: Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy. Nature 362:250–255, 1993

    Google Scholar 

  184. Zhu N et al: Systemic gene expression after intravenous DNA delivery into adult mice. Science 261:209–211, 1993

    Google Scholar 

  185. Cardiff RD, Miller WJ: Transgenic mouse models of mammary tumorigenesis. Cancer Surveys 16:97–113, 1993

    Google Scholar 

  186. Bieche I et al: Loss of heterozygosity of the L-myc oncogene in human breast tumors. Hum Genet 85:101–105, 1990

    Google Scholar 

  187. Mars W et al: Genomic changes on the short arm of human chromosome 1 in breast cancer. Cancer Detec Prev 15:145–149, 1991

    Google Scholar 

  188. Genuardi M, Tshirira H, Anderson DE: Distal deletion of chromosome 1 in ductal carcinoma of the breast. Am J Hum Genet 45:73–82, 1989

    Google Scholar 

  189. Chen P-L et al: Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell 58:1193–1198, 1989

    Google Scholar 

  190. Devilee P et al: At least four different chromosomal regions are involved in loss of heterozygosity in human breast carcinoma. Genomics 5:554–560, 1989

    Google Scholar 

  191. Knyazev PG et al: Loss of heterozygosity at chromosome 17p is associated withher-2 amplification and lack of nodal involvement in breast cancer. Int J Cancer 53:11–16, 1993

    Google Scholar 

  192. Mackay JM et al: Allele loss on short arm of chromosome 17 in breast cancers. Lancet 11:1384–1385, 1988

    Google Scholar 

  193. Sato T et al: Allelotype of breast cancer: Cumulative allele losses promote tumor progression in primary breast cancer. Cancer Res 50:7184–7189, 1990

    Google Scholar 

  194. Lee W-H et al: Purification, biochemical characterization, and biological function of human esterase D. Proc Natl Acad Sci USA 83:6790–6794, 1986

    Google Scholar 

  195. Radford DM et al: Allelic loss on chromosome 17 in ductal carcinoma in situ of the breast. Cancer Res 53:2947–2949, 1993

    Google Scholar 

  196. Milner BJ et al: Linkage studies with 17q and 18q markers in a breast/ovarian cancer family. Am J Hum Genet 52:761–766, 1993

    Google Scholar 

  197. Lindblom A et al: Four separate regions on chromosome 17 show loss of heterozygosity in familial breast carcinomas. Hum Genet 91:6–12, 1993

    Google Scholar 

  198. Coles C et al: Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis. Lancet 336:761–763, 1990

    Google Scholar 

  199. Davidoff AM et al: Genetic basis for p53 overexpression in human breast cancer. Proc Natl Acad Sci USA 88:5006–5010, 1991

    Google Scholar 

  200. Thompson AM et al: p53 gene expression and chromosome 17p allele loss in breast cancer. Br J Cancer 61:74–78, 1990

    Google Scholar 

  201. Varley JM, Brammar WJ, Lane DP: Loss of chromosome 17p13 sequences and mutation of p53 in human breast carcinomas. Oncogene 6:413–421, 1991

    Google Scholar 

  202. Chen L et al: Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer. Proc Natl Acad Sci USA 88:3847–3851, 1991

    Google Scholar 

  203. Sato T et al: Accumulation of genetic alterations and progression of primary breast cancer. Cancer Res 51:5794–5799, 1991

    Google Scholar 

  204. Brodeur GM, Sekhon GS, Goldstein MN: Chromosomal aberrations in human neuroblastomas. Cancer 40:2256–2263, 1977

    Google Scholar 

  205. Weith A et al: Neuroblastoma consensus deletion maps to 1p36.1-2. Genes Chromosomes Cancer 1:159–166, 1989

    Google Scholar 

  206. Cannon-Albright LA et al: Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science 258:1148–1152, 1992

    Google Scholar 

  207. Petty EM et al: Molecular definition of a chromosome 9p21 germ-line deletion in a woman with multiple melanomas and a plexiform neurofibroma: Implications for 9p tumor-suppressor gene(s). Am J Hum Genet 53:94–104, 1993

    Google Scholar 

  208. Larsson C et al: Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332:85–87, 1988

    Google Scholar 

  209. Gailani MR et al: Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. Cell 69:111–117, 1992

    Google Scholar 

  210. Cohen AJ et al: Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med 301:592–595, 1979

    Google Scholar 

  211. Leach FS et al: Mutational analysis ofmutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225, 1993

    Google Scholar 

  212. Kamb A et al: A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440, 1994

    Google Scholar 

  213. Nobori T et al: Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368:753–756, 1994

    Google Scholar 

  214. Serrano M, Hannon GJ, Beach D: A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707, 1993

    Google Scholar 

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  1. Center for Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center, 78245-3207, San Antonio, TX, USA

    Laura A. Cox, Gang Chen & Eva Y. -H. P. Lee

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  1. Laura A. Cox
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  2. Gang Chen
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Cox, L.A., Chen, G. & Lee, E.Y.H.P. Tumor suppressor genes and their roles in breast cancer. Breast Cancer Res Tr 32, 19–38 (1994). https://doi.org/10.1007/BF00666203

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