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P53, apoptosis, and breast cancer

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Abstract

Wild-type p53 is a tumor suppressor gene that plays a central role in maintaining the genetic integrity of the cell by preventing cells with damaged DNA from further proliferation. Mutation and deletion of p53 are the most common genetic defects seen in clinical cancer. About 40% of breast carcinomas show high levels of stabilized, often mutant, p53 protein in their cells as detected by immunohistochemistry. p53-related defects in tumor cells correlate with a poor prognosis and may also indicate a poor response to chemotherapy. In experimental systems, the p53 status of cells is important in determining their sensitivity to radiation and chemotherapeutic drugs. Cells with functional p53 die by apoptosis, whilst similar cells lacking p53 function continue to proliferate, perpetuating potentially oncogenic mutations. Not only may p53 status be a marker of the biological aggressiveness of individual tumors and of their likely response to therapy, but restoration of normal p53 function is itself already a goal of cancer therapy.

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References

  1. D. P. Lane and L. V. Crawford (1979). T antigen is bound to a host protein in SV40-transformed cells.Nature 278:261–263.

    PubMed  Google Scholar 

  2. F. Chang, S. Syrjanen, A. Tervahauta, and K. Syrjanen (1993). Tumorigenesis associated with the p53 tumor suppressor gene.Br. J. Cancer 68:653–661.

    PubMed  Google Scholar 

  3. M. B. Kastan, O. Onyekwere, D. Sidransky, B. Vogelstein,R. W. Craig (1991). Participation of p53 protein in the cellular response to DNA damage.Cancer Res. 51:6304–6311.

    PubMed  Google Scholar 

  4. A. R. Clarke, C. A. Purdie, D. J. Harrison, R. G. Morris, C. C. Bird, M. L. Hooper, and A. H. Wyllie (1993). Thymocyte apoptosis induced by p53-dependent and independent pathways.Nature 362:849–852.

    PubMed  Google Scholar 

  5. D. Malkin (1994). p53 and the Li-Fraumeni syndrome.Biochim. Biophys. Acta 1198:197–213.

    PubMed  Google Scholar 

  6. D. Malkin, F. P. Li, L. C. Strong, J. F. Fraumeni, C. E. Nelson, D. H. Kim, J. Kassel, M. G. Gryka, F. Z. Bischoff, M. A. Tainsky, and S. H. Friend (1990). Germline p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms.Science 250:1233–1238.

    PubMed  Google Scholar 

  7. L. A. Donehower and A. Bradley (1993). The tumor suppressor p53.Biochim. Biophys. Acta 1155:181–205.

    PubMed  Google Scholar 

  8. S. M. Picksley and D. P. Lane (1994). p53 and Rb: their cellular roles.Curr. Opin. Cell Biol. 6:853–858.

    PubMed  Google Scholar 

  9. Y. Cho, S. Gorina, P. D. Jeffrey, and N. P. Pavletich (1994). Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.Science 265:346–355.

    PubMed  Google Scholar 

  10. S. M. Picksley and D. P. Lane (1993). The p53-mdm2 autoregulatory feedback loop: a paradigm for the regulation of growth control by p53.Bioessays 15:689–690.

    PubMed  Google Scholar 

  11. J. D. Oliner, K. W. Kinzler, P. S. Meltzer, D. L. George, and B. Vogelstein (1992). Amplification of a gene encoding a p53 associated protein in human sarcomas.Nature 358:80–83.

    PubMed  Google Scholar 

  12. J. A. Pietenpol, T. Tokino, S. Thiagalingam, W. S. El-Deiry, K. W. Kinzler, and B. Vogelstein (1994). Sequence-specific transcriptional activation is essential for growth suppression by p53.PNAS 91:1998–2002.

    PubMed  Google Scholar 

  13. B. C. Hann and D. P. Lane (1995). The dominating effect of mutant p53.Natl. Genet. 9:221–222.

    Google Scholar 

  14. D. M. Barnes, A. M. Hanby, C. E. Gillett, S. Mohammed, S. Hodgson, L. G. Bobrow, I. M. Leigh, T. Purkis, C. MacGeoch, N. K. Spurr,et al. (1992). Abnormal expression of wild type p53 protein in normal cells of a cancer family patient.Lancet 340:259–263.

    PubMed  Google Scholar 

  15. B. Vojtesek and D. P. Lane (1993). Regulation of p53 protein expression in human breast cancer cell lines.J. Cell Sci. 105:607–612.

    PubMed  Google Scholar 

  16. D. P. Lane (1992). p53, guardian of the genome.Nature 358:15–16.

    PubMed  Google Scholar 

  17. D. Wynford-Thomas, J. A. Bond, F. S. Wyllie, and C. J. Jones (1995). Does Telomere Shortening Drive Selection for p53 Mutation in Human Cancer?Mol. Carcinogen. 12:119–123.

    Google Scholar 

  18. S. W. Lowe, H. E. Ruley, T. Jacks, and D. E. Housman (1993). p53-dependent apoptosis modulates the cytotoxicity of anticancer agents.Cell 74:957–967.

    PubMed  Google Scholar 

  19. S. W. Lowe, S. Bodis, A. McClatchey, L. Remington, H. E. Ruley, D. E. Fisher, D. E. Housman, and T. Jacks (1994). p53 status and the efficacy of cancer therapyin vivo.Science 266:807–810.

    PubMed  Google Scholar 

  20. T. Fujiwara, E. A. Grimm, T. Mukhopadhyay, W. Zhang, L. B. Owen-Schaub, and J. A. Roth (1994). Induction of chemosensitivity in human lung cancer cellsin vivo by adenovirus-mediated transfer of the wild-type p53 gene.Cancer Res. 54:2287–2291.

    PubMed  Google Scholar 

  21. O. R. Koechli, G. N. Schaer, B. Seifert, R. Hornung, U. Haller, U. Eppenberger, and H. Mueller (1994). Mutant p53 protein associated with chemosensitivity in breast cancer specimens.Lancet 344:1647–1648.

    Google Scholar 

  22. R. D. Petty, I. A. Cree, L. A. Sutherland, E. M. Hunter, D. P. Lane, P. E. Preece, and P. E. Andreotti (1994). Expression of the p53 tumor suppressor gene product is a determinant of chemosensitivity.Biochem. Biophys. Res. Commun. 199:264–270.

    PubMed  Google Scholar 

  23. D. C. Allred, G. M. Clark, S. A. W. Fuqua, R. M. Elledge, S. G. Hilsenbeck, P. M. Ravdin, D. Yee, G. C. Chamness, and C. K. Osborne (1993). Overexpression of p53 in node-positive breast cancer.Breast Cancer Res. Treat. 27:131.

    Google Scholar 

  24. A. Makris, T. J. Powles, M. Dowsett, and C. Allred (1995). p53 protein overexpression and chemosensitivity in breast cancer.Lancet 345:1181–1182.

    Google Scholar 

  25. M. C. Mathieu, S. Koscielny, M. L. Lebihan, M. Spielmann, and R. Arriagada (1995). p53 protein overexpression and chemosensitivity in breast cancer.Lancet 345:1182.

    Google Scholar 

  26. F. J. Chang, S. Syrjanen, and K. Syrjanen (1995). Implications of the p53 tumor-suppressor gene in clinical oncology.J. Clin. Oncol. 13:1009–1022.

    PubMed  Google Scholar 

  27. R. Mazars, L. Spinardi, M. Bencheikh, J. Simonylafontaine, P. Jeanteur, and C. Theillet (1992). p53 mutations occur in aggressive breast cancer.Cancer Res. 52:3918–3923.

    PubMed  Google Scholar 

  28. J. E. Eyfjord, S. Thorlacius, M. Steinarsdottir, R. Valgardsdottir, H. M. Ogmundsdottir, and K. Anamthawat-Jonsson (1995). p53 abnormalities and genomic instability in primary human breast carcinomas.Cancer Res. 55:646–651.

    PubMed  Google Scholar 

  29. G. Cattoretti, F. Rilke, S. Andreola, L. D'Amato, and D. Delia (1988). p53 expression in breast cancer.Int. J. Cancer 41:178–183.

    PubMed  Google Scholar 

  30. C. A. Midgley, C. Fisher, J. Bartek, B. Vojtesek, D. P. Lane, and D. M. Barnes (1992). Analysis of p53 expression in human tumors: an antibody raised against human p53 expressed inEscherichia coli.J. Cell Sci. 101:183–189.

    PubMed  Google Scholar 

  31. C. J. Fisher, C. E. Gillett, B. Vojtesek, D. M. Barnes, and R. R. Millis (1994). Problems with p53 immunohistochemical staining: the effect of fixation and variation in the methods of evaluation.Br. J. Cancer 69:26–31.

    PubMed  Google Scholar 

  32. D. C. Allred, G. M. Clark, R. Elledge, S. A. W. Fuqua, R. W. Brown, G. C. Chamness, C. K. Osborne, and W. L. McGuire (1993). Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer.JNCI 85:200–206.

    PubMed  Google Scholar 

  33. D. M. Barnes, E. A. Dublin, C. J. Fisher, D. A. Levison, and R. R. Millis (1993). Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis?Hum. Pathol. 24:469–476.

    PubMed  Google Scholar 

  34. T. Haerslev and G. K. Jacobsen (1995). An immunohistochemical study of p53 with correlations to histopathological parameters, c-erbB-2, proliferating cell nuclear antigen, and prognosis.Hum. Pathol. 26:295–301.

    PubMed  Google Scholar 

  35. P. A. Humphrey, D. W. Franquemont, W. A. Geary, B. Kerns, J. D. Iglehart, and J. R. Marks (1994). Immunodetection of p53 protein in noninvasive epithelial proliferative breast disease.Appl. Immunoistochem. 2:22–28.

    Google Scholar 

  36. L. G. Bobrow, L. C. Happerfield, W. M. Gregory, and R. R. Millis (1995). Ductal carcinomain situ: assessment of necrosis and nuclear morphology and their association with biological markers.J. Pathol. 176:333–342.

    PubMed  Google Scholar 

  37. F. P. O'Malley, C. L. Vnencak-Jones, W. D. Dupont, F. Parl, S. Manning, and D. L. Page (1994). p53 mutations are confined to the comedo type ductal carcinomain situ of the breast. Immunohistochemical and sequencing data.Lab. Invest. 71:67–72.

    PubMed  Google Scholar 

  38. R. Holland, J. L. Peterse, R. R. Millis, V. Eusebi, D. Faverly, M. J. van de Vijver, and B. Zafrani (1994). Ductal carcinomain situ: a proposal for a new classification.Sem. Diag. Pathol. 11:167–180.

    Google Scholar 

  39. B. Vojtesek, C. J. Fisher, D. M. Barnes, and D. P. Lane (1993). Comparison between p53 staining in tissue sections and p53 protein levels measured by and ELISA technique.Br. J. Cancer 67:1254–1258.

    PubMed  Google Scholar 

  40. A. Borg, J. Lennerstrand, M. Stenmark-Askmalm, M. Ferno, A. Brisfors, A. Ohrvik, O. Stal, D. Killander, D. Lane, and J. Brundell (1995). Prognostic significance of p53 overexpression in primary breast cancer; a novel luminometric immunoassay applicable on steriod receptor cytosis.Br. J. Cancer 67:1254–1258.

    Google Scholar 

  41. A. M. Davidoff, B. J. M. Kerns, J. D. Iglehart, and J. R. Marks (1991). Maintenance of p53 alterations throughout breast cancer progression.Cancer Res. 51:2605–2610.

    PubMed  Google Scholar 

  42. J. Bartkova, J. Bartek, B. Vojtesek, J. Lukas, A. Rejthar, J. Kovarik, R. R. Millis, D. P. Lane, and D. M. Barnes (1993). Immunochemical analysis of the p53 oncoprotein in matched primary and metastatic human tumors.Eur. J. Cancer 29A:881–886.

    PubMed  Google Scholar 

  43. A. H. McCann, A. Kirley, D. N. Carney, N. Corbally, H. M. Magee, G. Keating, and P. A. Dervan (1995). Amplification of the mdm2 gene in human breast cancer and its association with mdm2 and p53 protein status.Br. J. Cancer 71:981–985.

    PubMed  Google Scholar 

  44. C. Cordon-Cardo, E. Latres, M. Drobnjak, M. R. Oliva, D. Pollack, J. M. Woodruff, V. Marechal, J. Chen, F. Murray, F. Brennan, and A. J. Levine (1994). Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas.Cancer Res. 54:794–799.

    PubMed  Google Scholar 

  45. H. Patterson, S. Gill, C. Fisher, M. G. Law, H. Jayatilake, C. D. M. Fletcher, M. Thomas, R. Grimer, B. A. Gusterson, and C. S. Cooper (1994). Abnormalties of the p53 mdm2 and DCC genes in human leiomyosarcomas.Br. J. Cancer 69:1052–1058.

    PubMed  Google Scholar 

  46. F. P. Li, J. F. Fraumeni, J. J. Mulvihill, W. A. Blattner, M. G. Dreyfus, M. A. Tucker, and R. W. Miller (1988). A cancer family syndrome in twenty-four kindreds.Cancer Res. 48:5358–5362.

    PubMed  Google Scholar 

  47. J. M. Birch, A. L. Hartley, K. J. Tricker, J. Prosser, A. Condie, A. M. Kelsey, M. Harris, P. H. Morris Jones, A. Binchy, D. Crowther, A. W. Craft, O. S. Eden, G. R. Evans, E. Thompson, J. R. Mann, J. Martin, E. L. D. Mitchell, and M. F. Santibanez-Koref (1994). Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.Cancer Res. 54:1298–1304.

    PubMed  Google Scholar 

  48. C. Cooper (1995) (personal communication).

  49. R. A. Eeleset al. (In preparation).

  50. C. MacGeoch, G. Turner, L. G. Bobrow, D. M. Barnes, D. T. Bishop, and N. K. Spurr (1995). Heterogeneity in Li-Fraumeni families: p53 mutation analysis and immunohistochemical staining.J. Med. Genet. 32:186–190.

    PubMed  Google Scholar 

  51. R. S. Camplejohn, P. Perry, S. V. Hodgson, G. Turner, A. Williams, C. Upton, C. MacGeoch, S. Mohammed, and D. M. Barnes (1995). A possible screening test for inherited p53-related defects based on the apoptotic reaponse of peripheral blood lymphocytes to DNA damage.Br. J. Cancer 72:654–662.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. ICRF Clinical Oncology Unit, Guy's Hospital, SE1 9RT, London

    Diana M. Barnes

  2. Richard Dimbleby Department of Cancer Research, UMDS, St. Thomas' Hospital, SE1 7EH, London

    Richard S. Camplejohn

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Barnes, D.M., Camplejohn, R.S. P53, apoptosis, and breast cancer. J Mammary Gland Biol Neoplasia 1, 163–175 (1996). https://doi.org/10.1007/BF02013640

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