Summary
Alterations in the p53 tumor suppressor gene are the most frequent genetic changes found in breast cancer, with an incidence reported in a range of 15 to 50%. The incidence of p53 alterations is approximately 15% for in situ carcinoma, while for invasive node-positive disease it is 2 to 3 times higher. This high rate of alteration suggests that the gene plays a central role in the development of breast cancer.
The p53 gene functions as a negative regulator of cell growth. Alterations in the gene lead to loss of its usual negative growth regulation and more rapid cell proliferation. Since p53 alteration can reflect a more advanced state of progression and a higher rate of proliferation, breast tumors that have a p53 alteration could have a greater probability of having micrometastasis. p53 alterations could therefore be a prognostic factor for recurrence after primary local therapy. Consistent with this hypothesis, several independent studies using different methodologies have found that breast tumors with altered p53 have a worse prognosis and are also more likely to have other poor prognostic factors.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 253:49–53, 1991
Bártek J, Bártková J, Voitesek B, Stasková Z, Rejthar A, Kovarik J, Lane DP: Patterns of expression of the p53 tumour suppressor in human breast tissues and tumours in situ and in vitro. Int J Cancer 46:839–844, 1990
Davidoff AM, Kerns B-JM, Iglehart JD, Marks JR: Maintenance of p53 alterations throughout breast cancer progression. Cancer Res 51:2605–2610, 1991
Osborne RJ, Merlo GR, Mitsudomi T, Venesio T, Liscia DS, Cappa APM, Chiba I, Takahashi T, Nau MM, Callahan R, Minna JD: Mutations in the p53 gene in primary human breast cancers. Cancer Res 51:6194–6198, 1991
Thor AD, Moore DH II, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch HT, Marcus JN, Schwartz L, Chen L-C, Mayall BH, Smith HS: Accumulation of p53 tumor suppressor gene protein: An independent marker of prognosis in breast cancers. J Natl Cancer Inst 84:845–855, 1992
Allred DC, Clark GM, Elledge RM, Fuqua SAW, Brown RW, Chamness GC, Osborne CK, McGuire WL: Accumulation of mutant p53 is associated with increased proliferation and poor clinical outcome in node-negative breast cancer. J Natl Cancer Inst 85:200–206, 1993
Runnebaum IB, Nagarajan M, Bowman M, Oto D, Sukumar S: Mutations in p53 as potential molecular markers for human breast cancer. Proc Natl Acad Sci USA 88:10657–10661, 1991
Mazars R, Spinardi L, BenCheikh M, Simony-Lafontaine J, Jeanteur P, Theillet C: p53 mutations occur in aggressive breast cancer. Cancer Res 52:3918–3923, 1992
Sommer SS, Cunningham J, McGovern RM, Saitoh S, Schroeder JJ, Wold LE, Kovach JS: Pattern of p53 gene mutations in breast cancers of women of the midwestern United States. J Natl Cancer Inst 84:246–252, 1992
Coles C, Condie A, Chetty U, Steel CM, Evans J, Prosser J: p53 mutations in breast cancer. Cancer Res 52:5291–5298, 1992
Moll UM, Riou G, Levine AJ: Two distinct mechanisms alter p53 in breast cancer: Mutation and nuclear exclusion. Proc Natl Acad Sci USA 89:7262–7266, 1992
Shaulsky G, Ben-Ze'ev A, Rotter V: Subcellular distribution of the p53 protein during the cell cycle of Balb/c 3T3 cells. Oncogene 5:1707–1711, 1990
Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51:6304–6311, 1991
Momand J, Zambetti GP, Olson DC, George D, Levine AJ: The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245, 1992
Linzer DIH, Levine AJ: Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52, 1979
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136, 1990
Mackay J, Steel CM, Elder PA, Forrest APM, Evans HJ: Allele loss on short arm of chromosome 17 in breast cancers. Lancet ii:1384–1385, 1988
Sato T, Akiyama F, Sakamoto G, Kasumi F, Nakamura Y: Accumulation of genetic alterations and progression of primary breast cancer. Cancer Res 51:5794–5799, 1991
Davidoff AM, Humphrey PA, Iglehart JD, Marks JR: Genetic basis for p53 overexpression in human breast cancer. Proc Natl Acad Sci USA 88:5006–5010, 1991
Rady P, Scinicariello F, Wagner RF Jr, Tyring SK: p53 mutations in basal cell carcinomas. Cancer Res 52:3804–3806, 1992
Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238, 1990
Børresen A-L, Andersen TI, Holm R, Eyfjörd J, Friend S: TP53 germline and somatic mutation in human breast cancer [abstract]. Breast Cancer Res Treat 23:136, 1992
Warren W, Eeles RA, Ponder BAJ, Easton DF, Averill D, Ponder MA, Anderson K, Evans AM, DeMars R, Love R, Dundas S, Stratton MR, Trowbridge P, Cooper CS, Peto J: No evidence for germline mutations in exons 5-9 of the p53 gene in 25 breast cancer families. Oncogene 7:1043–1046, 1992
Prosser J, Elder PA, Condie A, MacFadyen I, Steel CM, Evans HJ: Mutations in p53 do not account for heritable breast cancer: A study in five affected families. Br J Cancer 63:181–184, 1991
Sidransky D, Tokino T, Helzlsouer K, Zehnbauer B, Rausch G, Shelton B, Prestigiacomo L, Vogelstein B, Davidson N: Inherited p53 gene mutations in breast cancer. Cancer Res 52:2984–2986, 1992
Lidereau R, Soussi T: Absence of p53 germ-line mutations in bilateral breast cancer patients. Human Genetics 89:250–252, 1992
Michalovitz D, Halevy O, Oren M: Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell 62:671–680, 1990
Kikuchi-Yanoshita R, Konishi M, Ito S, Seki M, Tanaka K, Maeda Y, Iino H, Fukayama M, Koike M, Mori T, Sakuraba H, Fukunari H, Iwama T, Miyaki M: Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and nonfamilial adenomatous polyposis patients. Cancer Res 52:3965–3971, 1992
Fujimoto K, Yamada Y, Okajima E, Kakizoe T, Sasaki H, Sugimura T, Terada M: Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res 52:1393–1398, 1992
de Fromentel CC, Soussi T: TP53 tumor suppressor gene: A model for investigating human mutagenesis. Genes Chrom Cancer 4:1–15, 1992
Soussi T, de Fromentel CC, May P: Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5:945–952, 1990
Orita M, Suzuki Y, Sekiya T, Hayashi K: Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5:874–879, 1989
Isola J, Visakorpi T, Holli K, Kallioniemi O-P: Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst 84:1109–1114, 1992
Iwaya K, Tsuda H, Hiraide H, Tamaki K, Tamakuma S, Fukutomi T, Mukai K, Hirohashi S: Nuclear p53 immunoreaction associated with poor prognosis of breast cancer. Jpn J Cancer Res 82:835–840, 1991
Davidoff AM, Herndon JE II, Glover NS, Kerns B-JM, Pence JC, Iglehart JD, Marks JR: Relation between p53 overexpression and established prognostic factors in breast cancer. Surgery 110:259–264, 1991
Ostrowski JL, Sawan A, Henry L, Wright C, Henry JA, Hennessy C, Lennard TJW, Angus B, Horne CHW: p53 expression in human breast cancer related to survival and prognostic factors: An immunohistochemical study. J Pathol 164:75–81, 1991
Cattoretti G, Rilke F, Andreola S, D'Amato L, Delia D: p53 expression in breast cancer. Int J Cancer 41:178–183, 1988
Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51:6304–6311, 1991
Lane DP: p53, guardian of the genome. Nature 358: 15–16, 1992
Law JC, Strong LC, Chidambaram A, Ferrell RE: A germ line mutation in exon 5 of the p53 gene in an extended cancer family. Cancer Res 51:6385–6387, 1991
Carbone D, Chiba I, Mitsudomi T: Polymorphism at codon 213 within the p53 gene. Oncogene 6:1691–1692, 1991
Buchman VL, Chumakov PM, Ninkina NN, Samarina OP, Georgiev GP: A variation in the structure of the protein-coding region of the human p53 gene. Gene 70:245–252, 1988
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Elledge, R.M., Fuqua, S.A.W., Clark, G.M. et al. The role and prognostic significance of p53 gene alterations in breast cancer. Breast Cancer Res Tr 27, 95–102 (1993). https://doi.org/10.1007/BF00683196
Issue Date:
DOI: https://doi.org/10.1007/BF00683196