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The Role of the RAS Oncogene in Human Mammary Cancer

  • Edward P. Gelmann
  • Connie Agnor
  • Marc E. Lippman
Part of the Serono Symposia, USA book series (SERONOSYMP)

Abstract

The cellular homologues, termed proto-oncogenes, of transforming genes transduced or activated by transforming retroviruses have been implicated in the etiology of a number of human cancers. Several specific mechanisms have been proposed in which proto-oncogenes cause cellular transformation. These mechanisms include point mutation (1–3), gene truncation (4), transcriptional activation (5), gene rearrangement (6,7), and gene amplification (8–10). More than 20 proto-oncogenes have been identified and fall into five general categories: (1) growth factors (e.g., sis [11] and perhaps int-2 [12]); (2) growth factor and hormone receptors (e.g., erbB [13], fms [14], and erbA [15]); (3) intracellular tyrosine (e.g.,src[161) and serine (e.g., mos [17]) kinases; (4) nuclear-associated oncogenes (e.g., fos [18], myc [19], and myb [20]); and, (5) G-protein-like molecules (e.g., ras [21]).

Keywords

Breast Cancer Mammary Carcinoma Autocrine Motility Factor Advanced Histologic Grade Harvey Murine Sarcoma Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Dhar R, Ellis R, Shih TY,Nucleotide sequence of the p21 transforming protein of Harvey murine sarcoma virus. Science 1982; 217: 934–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Reddy EP, Reynolds RK, Santos E, Barbacid M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 1982; 300: 149–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Capon DJ, Chen EY, Levinson AD, Seeburg PH, Goeddel DV. Complete nucleotide sequence of the T24 human bladder carcinoma oncogene and its normal homologue. Nature 1983; 302: 33–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Leder P, Battey J, Lenoir G,Translocations among antibody genes in human cancer. Science 1983; 222: 765–71.PubMedCrossRefGoogle Scholar
  5. 5.
    Nishikura K, ar-Rushdi A, Erikson J, Watt R, Rovera G, Croce C. Differential expression of the normal and of the translocated human c-myc oncogenes in B cells. Proc Natl Acad Sci USA 1983; 80: 4822–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukemia. Nature 1985; 315: 550–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Bakhshi A, Jensen JP, Goldman P,Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985; 41: 899–906.PubMedCrossRefGoogle Scholar
  8. 8.
    Dalla Favera R, Wong-Staal F, Gallo RC. Onc gene amplification in promyelocytic leukaemia cell line HL-60 and primary leukaemic cells of the same patient. Nature 1982; 299: 61–3.CrossRefGoogle Scholar
  9. 9.
    Alitalo K, Schwab M, Lin C, Varmus H, Bishop J. Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci USA 1982; 80: 1707–11.CrossRefGoogle Scholar
  10. 10.
    Schwab M, Ellison J, Busch M, Rosenau W, Varmus H, Bishop JM. Enhanced expression of the human gene N-myc consequent to amplification of DNA may contribute to malignant progression of neuroblastoma. Proc Natl Acad Sci USA 1984; 81: 4940–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Waterfield MD, Scrace G, Whittle N,Platelet-derived growth factor is structurally related to the putative transforming protein of simian sarcoma virus. Nature 1983; 304: 35–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Dickson C, Peters G. Potential oncogene product related to growth factors. Nature 1987; 326: 833.PubMedCrossRefGoogle Scholar
  13. 13.
    Downward J, Yarden Y, Mayes E, et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 1984; 307: 521–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Sherr CJ, Rettenmeier CW, Sacca R, Roussel MF, Look AT, Stanley ER. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocytic growth factor, CSF-1. Cell 1985; 41: 665–76.PubMedCrossRefGoogle Scholar
  15. 15.
    Sap J, Munoz A, Damm K, The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature 1986; 324: 635–40.PubMedCrossRefGoogle Scholar
  16. 16.
    Sefton BM, Hunter T, Beemon E, Eckhart W. Evidence that the phosphorylation of tyrosine is essential for transformation by Rous sarcoma virus. Cell 1980; 20: 807–16.PubMedCrossRefGoogle Scholar
  17. 17.
    Blair DG, Oskarsson MK, Seth A,Analysis of the transforming potential of the human homolog of mos. Cell 1986; 46: 785–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Sambucetti LC, Curran T. The fos protein complex is associated with DNA in isolated nuclei and binds to DNA cellulose. Science 1986; 234: 1417–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Persson H, Leder P. Nuclear localization and DNA binding properties of a protein expressed by human c-myc oncogene. Science 1984; 225: 718–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Klempnauer K-H, Symonds G, Evan GI, Bishop JM. Subcellular localization of proteins encoded by oncogenes of avian myeloblastosis virus and avian leukemia virus E26 and by the chicken c-myb gene. Cell 1984; 37: 537–47.PubMedCrossRefGoogle Scholar
  21. 21.
    Hurley JB, Simon MI, Teplow DB, Robishaw JD, Gilman AG. Homologies between signal transducing G proteins and ras gene products. Science 1984; 226: 860–2.PubMedCrossRefGoogle Scholar
  22. 22.
    O’Brien SJ, Nash WG, Goodwin JL, Lowy DR, Chang EH. Dispersion of the ras family of transforming genes to four different chromosomes in man. Nature 1983; 302: 839–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Ryan J, Barker PE, Shimizu K, Wigler M, Ruddle F. Chromosomal assignment of a family of human oncogenes. Proc Natl Acad Sci USA 1983; 80: 4460–3.PubMedCrossRefGoogle Scholar
  24. 24.
    Hall A, Marshall CJ, Spurr NK, Weiss RA. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras family located on chromosome 1. Nature 1983; 303: 396–400.PubMedCrossRefGoogle Scholar
  25. 25.
    Lowe DG, Capon DJ, Delwart E, Sakaguchi A, Naylor SL, Goeddel DV. Structure of the human and murine R-ras genes, novel genes closely related to ras proto-oncogenes. Cell 1987; 48: 137–46.PubMedCrossRefGoogle Scholar
  26. 26.
    Kataoka T, Powers S, McGill C, et al. Genetic analysis of yeast RAS1 and RAS2 genes. Cell 1984; 37: 437–45.PubMedCrossRefGoogle Scholar
  27. 27.
    Defeo-Jones D, Scolnick E, Koller R, Dhar R. ras-Related gene sequences identified and isolated from Saccharomyces cerevisiae. Nature 1983; 306: 707–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Tatchell K, Chaleff D, Defeo-Jones D, Scolnick E. Requirement of either of a pair of ras-related genes of Saccharomyses cerevisiae for spore viability. Nature 1984; 309: 523–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Reymond CD, Gomer RH, Mehdy MC, Firtel RA. Developmental regulation of a Dictyostelium gene encoding a protein homologous to mammalian ras protein. Cell 1984; 39: 141–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Powers S, Kataoka T, Fasano 0,Genes in S. cerevisiae encoding proteins with domains homologous to the mammalian ras proteins. Cell 1984; 36: 607–12.PubMedCrossRefGoogle Scholar
  31. 31.
    Broek D, Samíly N, Fasano 0,Differential activation of yeast adenylate cyclase by wild-type and mutant ras proteins. Cell 1985; 41: 763–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Toda T, Uno I, Ishikawa T,In yeast, RAS proteins are controlling elements of adenylate cyclase. Cell 1985; 40: 27–36.PubMedCrossRefGoogle Scholar
  33. 33.
    Defeo-Jones D, Tatchell K, Robinson LC,Mammalian and yeast ras gene products: biological function in their heterologous systems. Science 1985; 228: 179–84.PubMedCrossRefGoogle Scholar
  34. 34.
    Kataoka T, Powers S, Cameron S, et al. Functional homology of mammalian and yeast RAS genes. Cell 1985; 40: 19–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Becker SK, Hattori S, Shih TY. The ras oncogene product p21 is not a regulatory component of adenylate cyclase. Nature 1985; 317: 71–2.CrossRefGoogle Scholar
  36. 36.
    Shih TY, Weeks MO, Gruss P, Dhar R, Oroszlan S, Scolnick E. Identification of a precursor in the biosynthesis of the p21 transforming protein of Harvey murine sarcoma virus. J Virol 1982; 42: 253–61.PubMedGoogle Scholar
  37. 37.
    Willingham MC, Pastan I, Shih TY, Scolnick EM. Localization of the src gene product of the Harvey strain of MSV to plasma membrane of transformed cells by electron microscopic immunocytochemistry. Cell 1980; 19: 1005–14.PubMedCrossRefGoogle Scholar
  38. 38.
    Sefton BM, Trowbridge IS, Cooper JA, Scolnick EM. The transforming proteins of Rous sarcoma virus, Harvey sarcoma virus and Abelson virus contain tightly bound lipid. Cell 1982; 31: 465–74.PubMedCrossRefGoogle Scholar
  39. 39.
    Willumsen BM, Christensen A, Hubbert NL, Papageorge AG, Lowy DR. The p21 ras c-terminus is required for transformation and membrane association. Nature 1984; 310: 583–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Dever TE, Glynias MJ, Merrick WC. GTP-binding domain: three consensus sequence elements with distinct spacing. Proc Natl Acad Sci USA 1987; 84: 1814–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Nishikura K, ar-Rushdi A, Erikson J, Watt R, Rovera G, Croce C. Differential expression of the normal and of the translocated human c-myc oncogenes in B cells. Proc Natl Acad Sci USA 1983; 80: 4822–6.PubMedCrossRefGoogle Scholar
  42. 42.
    McCormick F, Clark BFC, lacour TFM, Kjeldgaard M, Norskov-Lauritsen L, Nyborg J. A model for the tertiary structure of p21, the product of the ras oncogene. Science 1985; 230: 78–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Walter M, Clark SG, Levinson AD. The oncogenic activation of human p21 ras by a novel mechanism. Science 1986; 233: 649–52.PubMedCrossRefGoogle Scholar
  44. 44.
    Sigel IS, Gibbs JB, D’Alonzo JS, Scolnick EM. Identification of effector residues and a neutralizing epitope of Ha-ras encoded p21. Proc Natl Acad Sci USA 1986; 83: 4725–9.CrossRefGoogle Scholar
  45. 45.
    Willumsen BM, Papageorge A, Kung H-F,Mutational analysis of the ras catalytic domain. Mol Cell Biol 1986; 6: 2646–54.PubMedGoogle Scholar
  46. 46.
    Yuasa Y, Srivastava SK, Dunn CY, Rhim JS, Reddy EP, Aaronson SA. Acquisition of transforming properties by alternative point mutations within c-bas/has human proto-oncogene. Nature 1983; 303: 775–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Perucho M, Goldfarb M, Shimizu K, Lama C, Fogh J, Wigler M. Human tumor-derived cell lines contain common and different transforming genes. Cell 1981; 27: 467–76.PubMedCrossRefGoogle Scholar
  48. 48.
    Der C, Finkel T, Cooper GM. Biological and biochemical properties of human rasH genes mutated at codon 61. Cell 1986; 44: 167–76.PubMedCrossRefGoogle Scholar
  49. 49.
    Fasano 0, Aldrich T, Tamanoi F, Taparowsky E, Furth M, Wigler M. Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc Natl Acad Sci USA 1984; 81: 4008–12.CrossRefGoogle Scholar
  50. 50.
    McGrath JP, Capon D, Goeddel DV, Levinson AD. Comparative biochemical properties of normal and activated human ras p21 protein. Nature 1984; 310: 644–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Gibbs JB, Sigal IS, Poe M, Scolnick EM. Intrinsic Gtpase activity distinguishes normal and oncogenic ras p21 molecules. Proc Natl Acad Sci USA 1984; 81: 5704–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Manne V, Bekesi E, Kung H-F. Ha-ras proteins exhibit Gtpase activity: point mutations that activate Ha-ras gene products result in decreased Gtpase activity. Proc Natl Acad Sci USA 1985; 82: 376–80.PubMedCrossRefGoogle Scholar
  53. 53.
    Lacal JC, Srivastava SK, Anderson PS, Aaronson SA. Ras p21 proteins with high and low Gtpase activity can efficiently transform Nih/3T3 cells. Cell 1986; 44: 609–17.PubMedCrossRefGoogle Scholar
  54. 54.
    Chang EH, Furth ME, Scolnick EM, Lowy DR. Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus. Nature 1982; 297: 479–83.PubMedCrossRefGoogle Scholar
  55. 55.
    Kraus MH, Yuasa Y, Aaronson SA. A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Proc Natl Acad Sci USA 1984; 81: 5384–8.PubMedCrossRefGoogle Scholar
  56. 56.
    McGrath JP, Capon DJ, Smith DH, et al. Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature 1983; 304: 501–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Spandidos DA, Agnantis NJ. Human malignant tumours of the breast, as compared to their respective normal tissue, have elevated expression of the Harvey ras oncogene. Anticancer Res 1984; 4: 269–72.PubMedGoogle Scholar
  58. 58.
    Agnantis NJ, Parissi P, Anagnostakis D, Spandidos DA. Comparative study of Harvey-ras oncogene expression with conventional clinicopathologic parameters of breast cancer. Oncology 1986; 43: 36–9.PubMedCrossRefGoogle Scholar
  59. 59.
    DeBortoli ME, Abou-Issa H, Haley BE, Cho-Chung YS. Amplified expression of p21 ras protein in hormone-dependent mammary carcinomas of humans and rodents. Biochem Biophys Res Commun 1985; 127: 699–706.PubMedCrossRefGoogle Scholar
  60. 60.
    Hand PH, Thor A, Wunderlich D, Muraro R, Caruso A, Schlom J. Monoclonal antibodies of predefined specificity detect activated ras gene expression in human mammary and colon carcinomas. Proc Natl Acad Sci USA 1984; 81: 5227–31.PubMedCrossRefGoogle Scholar
  61. 61.
    Tanaka T, Slamon D, Battifora H, Cline MJ. Expression of p21 ras oncoproteins in human cancers. Cancer Res 1986; 46: 1465–70.PubMedGoogle Scholar
  62. 62.
    Theillet C, Lidereau R, Escot C, et al. Loss of a c-H-ras-1 allele and aggressive human primary breast carcinomas. Cancer Res 1986; 46: 4776–81.PubMedGoogle Scholar
  63. 63.
    Ohuchi N, Thor A, Page DL, Hand PH, Halter S, Schlom J. Expression of the 21,000 molecular weight ras protein in a spectrum of benign and malignant human mammary tissues. Cancer Res 1986 46: 2511–9.PubMedGoogle Scholar
  64. 64.
    Lidereau R, Escot C, Theillet C, et al. High frequency of rare alleles of the human c-Ha-ras-1 proto-oncogene in breast cancer patients. J Natl Cancer Inst 1986; 77: 697–701.PubMedGoogle Scholar
  65. 65.
    Graham KA, Richardson CL, Minden MD, Trent JM, Buick RM. Varying degrees of amplification of the N-ras oncogene in the human breast cancer cell line MCF-7. Cancer Res 1985; 45: 2201–5Google Scholar
  66. 66.
    Gullino P, Pettigrew HM, Grantham FH. N-nitrosomethylurea as mammary gland carcinogen in rats. J Natl Cancer Inst 1975; 54: 401–14.PubMedGoogle Scholar
  67. 67.
    Sukumar S, Notario V, Martin-Zanca D, Barbacid M. Induction of mammary carcinomas in rats by nitrosomethylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature 1983; 308: 658–61.CrossRefGoogle Scholar
  68. 68.
    Zarbl H, Sukumar S, Arthur AV, Martin-Zanca D, Barbacid M. Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. Nature 1985; 315: 382–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Chandler VL, Maler BA, Yamamoto KR. DNA sequences bound specifically by glucocorticoid receptor in vitro render a heterologous promoter hormone responsive in vivo. Cell 1983; 33: 489–99.PubMedCrossRefGoogle Scholar
  70. 70.
    Stewart TA, Pattengale PK, Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 1984; 38: 627–37.PubMedCrossRefGoogle Scholar
  71. 71.
    Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 1987; 49: 46575.CrossRefGoogle Scholar
  72. 72.
    Andres A-C, Schonenberger C-A, Groner B, Hennighausen L, LeMeur M, Gerlinger P. Ha-ras oncogene expression directed by a milk protein gene promoter: tissue specificity, hormonal regulation, and tumor induction in transgenic mice. Proc Natl Acad Sci USA 1987; 84: 1299303Google Scholar
  73. 73.
    Bates S, Dickson R, McManaway M, Lippman ME. Characterization of estrogen-responsive transforming activity in human breast cancer cell lines. Cancer Res 1986; 46: 1703–17.Google Scholar
  74. 74.
    Huff KK, Lippman ME, Spencer EM, Kaufman D, Dickson RB. Human breast cancer cells secrete an insulin-like growth factor I-related polypeptide. Cancer Res 1986; 46: 4613–9.PubMedGoogle Scholar
  75. 75.
    Bronzert D, Pantazis P, Antoniades H, et al. Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines. Proc Natl Acad Sci USA 1987; 84: 5763–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Swain S, Dickson R, Lippman ME. Anchorage-independent epithelial colony-stimulating activity in human breast cancer cell lines. Proc Am Assoc Cancer Res 1986; 27: 844.Google Scholar
  77. 77.
    Bano M, Salomon DS, Kidwell WR. Purification of a mammary-derived growth factor from human milk and mammary tumors. J Biol Chem 1986; 260: 5745–52.Google Scholar
  78. 78.
    Liotta L, Mandler R, Murano G, et al. Tumor cell autocrine motility factor. Proc Natl Acad Sci USA 1986; 83: 3302–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Dickson RB, McManaway ME, Lippman ME. Estrogen-induced factors of breast cancer cells partially replace estrogen to promote tumor growth. Science 1986; 232: 1540–3.PubMedCrossRefGoogle Scholar
  80. 80.
    Kasid A, Lippman ME, Papageorge AG, Lowy DR, Gelmann EP. Transfection of v-rasH DNA into MCF-7 human breast cancer cells bypasses dependence on estrogen for tumorigenicity. Science 1985; 228: 725–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Dickson RB, Kasid A, Huff KK, et al. Activation of growth factor secretion in tumorigenic states of breast cancer induced by 17Bestradiol or v-Ha-ras oncogene. Proc Natl Acad Sci USA 1987; 84: 837–41.PubMedCrossRefGoogle Scholar
  82. 82.
    Albini A, Graf J, Kitten GT,17B-estradiol regulates and v-Ha-ras transfection constitutively enhances MCF7 breast cancer cell interactions with basement membrane. Proc Natl Acad Sci USA 1986; 83: 8182–6.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Edward P. Gelmann
    • 1
  • Connie Agnor
    • 1
  • Marc E. Lippman
    • 1
  1. 1.Medical Breast Cancer SectionNational Cancer InstituteBethesdaUSA

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