Breast Cancer Research and Treatment

, Volume 61, Issue 1, pp 33–43

p21WAF1/CIP1 Expression in breast cancers: associations with p53 and outcome

  • Ann D. Thor
  • Shuquing Liu
  • Dan H. Moore II
  • Qiuju Shi
  • Susan M. Edgerton
Article

Abstract

p21WAF1/CIP1 is transcriptionally activated by wt p53 and inhibits G1 associated cyclins, a major mechanism by which p53 inhibits cellular proliferation. Archival breast cancers (798) with a median follow-up of 16.3 years were used to explore the prognostic value of p2l immunohistochemical analyses. p21 immunostaining was detected in the majority (726/798: 91%) of breast cancers as well as adjacent in situ carcinomas (125/170: 74%), hyperplastic lesions (140/349: 40%) and normal breast epithelium adjacent to carcinoma (3/89: 3%). Complete immunonegativity was observed in only 9% of invasive cancers and was associated with p53 immunopositivity (p<0.05).

Univariate analysis of all patients showed that p21 negativity was associated with a longer disease specific survival (relative risk (RR) 1.5). Node positive p21 – patients also showed a longer disease free and disease specific survival as compared to tumor p21+ patients. In node negative patients, p53 positivity but not p21 alone, was significantly associated with a shortened disease free survival (RR = 1.6). Node negative patients who were p53 + p21−, in particular had the shortest disease free survival compared to other p53, p21 subgroups (i.e., p21 negativity was associated with a worse outcome). Multivariate analysis of lymph node negative patients (n>300) demonstrated that tumor size and tumor grade were independently predictive of outcome, whereas neither p53 nor p21 were significant. For node positive patients, p21 positivity (p=0.05), p53 positivity (p=0.03), a higher number of positive nodes, larger tumor size, steroid receptor negativity, high proliferation rate, and erbB-2 expression were each independently associated with poor outcome.

In summary, p21 negativity was inversely correlated with p53 immunopositivity in the majority of cases. p21 negative tumor patients had an improved outcome if they were node positive, whereas p21 status was not significantly associated with survival in node negative patients. This observation may be due to the reported ‘uncoupling of S phase and mitosis’ associated with a loss of p21 expression which may result in enhanced sensitivity to chemotherapy.

breast cancer p21WAF1/CIP1 p53 prognosis 

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References

  1. 1.
    Ernberg IT: Oncogenes and tumor growth factors in breast cancer. A minireview. Acta Oncol 29(3): 331–334, 1990Google Scholar
  2. 2.
    Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, Barcos M, Cirrincione C, Edgerton S, Allred C, North L, Liu ET: erbB-2, p53 and the efficacy of adjuvant therapy in lymph node positive breast cancer. J Natl Cancer Inst 90: 1–16, 1998Google Scholar
  3. 3.
    Barbareschi M: Prognostic value of the immunohistochemical expression of p53 in breast carcinomas: a review of the literature involving over 9000 patients. Applied Immunohistochemistry 4: 106–116, 1996Google Scholar
  4. 4.
    McDonald ER III, Wu GS, Waldman T, El-Deiry W: Repair defect in p21 WAF1/CIP1 –/– human cancer cells Cancer Res 56: 2250–2255, 1996PubMedGoogle Scholar
  5. 5.
    Marx J: New tumor suppressor may rival p53. Science 264: 344–345, 1994PubMedGoogle Scholar
  6. 6.
    Geradts J, Wilson PA: High frequency of aberrant p16 (INK4A) expression in human breast cancer. Am J Pathol 149: 15–20, 1996PubMedGoogle Scholar
  7. 7.
    Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, Daling JR, Roberts JM: Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 3(2): 222–225, 1997PubMedGoogle Scholar
  8. 8.
    Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, Franssen E, Pritchard KI, Slingerland JM: Decreased levels of the cell-cycle inhibitor p27Kipl protein: prognostic implications in primary breast cancer. Nat Med 3(2): 227–230, 1997PubMedGoogle Scholar
  9. 9.
    Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup M, Pagano M: Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3(2): 231–234, 1997PubMedGoogle Scholar
  10. 10.
    Steeg PS, Abrams JS: Cancer prognostics: past, present and p27. Nat Med 3(2): 152–154, 1997PubMedGoogle Scholar
  11. 11.
    Thor AD, Moore DH II, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch FIT, Marcus JN, Schwartz L, Chen LC, 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, 1992PubMedGoogle Scholar
  12. 12.
    Stenmark-Askmalm M, Stal O, Olsen K, Nordenskjold B: p53 as a prognostic factor in stage I breast cancer. South-East Sweden Breast Cancer Group. Br J Cancer 72(3): 715–719, 1995PubMedGoogle Scholar
  13. 13.
    Linn SC, Honkoop AH, Hoekman K, van der Valk P, Pinedo HM, Giaccone G: p53 and P-glycoprotein are often coexpressed and are associated with poor prognosis in breast cancer. Br J Cancer 74(1): 63–68, 1996PubMedGoogle Scholar
  14. 14.
    Patel DD, Bhatavdekar JM, Chikhlikar PR, Ghosh N, Suthar TP, Shah NG, Mehta RH, Balar DB: Node negative breast carcinoma: hyperprolactinemia and/or overexpression of p53 as an independent predictor of poor prognosis compared to newer and established prognosticators. J Surg Oncol 62(2): 86–92, 1996PubMedGoogle Scholar
  15. 15.
    Kovach JS, Hartmann A, Blaszyk H, Cunningham J, Schaid D, Sommer SS: Mutation detection by highly sensitive methods indicates that p53 gene mutations in breast cancer can have important prognostic value. Proc Natl Acad Sci USA 93(3): 1093–1096, 1996PubMedGoogle Scholar
  16. 16.
    Wakasugi E, Kobayashi T, Tamaki Y, Ito Y, Miyashiro I, Komoike Y, Takeda T, Shin E, Takatsuka Y, Kikkawa N, Monden T, Monden M: p21 (Waf1/Cip1) and p53 protein expression in breast cancer. Am J Clin Pathol 107(6): 684–691, 1997PubMedGoogle Scholar
  17. 17.
    Andersen TI, Holm R, Nesland JM, Heimdal KR, Ottestad L, Brresen AL: Prognostic significance of TP53 alterations in breast carcinoma. Br J Cancer 68(3): 540–548, 1993PubMedGoogle Scholar
  18. 18.
    Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D: p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704, 1993PubMedGoogle Scholar
  19. 19.
    EI-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Winman KG, Mercer WE, Kastan MB, Kohn K, Elledge SJ, Kinzier KW, Vogeistein B: WAF-1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54(5): 1169–1174, 1994PubMedGoogle Scholar
  20. 20.
    Lukas J, Groshen S, Saffari B, Nui N, Reles A,WenWH, Felix J, Johns LA, Hall FL, Press MF:WAF1/Cip1 gene polymorphism and expression in carcinomas of the breast, ovary, and endometrium. Am J Pathol 150(1): 167–175, 1997PubMedGoogle Scholar
  21. 21.
    Sheikh MS, Li XS, Chen JC, Shao ZM, Ordonez JV, Fontana JA: Mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma: role of p53-dependent and independent signal transduction pathways. Oncogene 9: 3407–3415, 1994PubMedGoogle Scholar
  22. 22.
    Michieli P, Chedid M, Lin D, Pierec JH, Mercer WE, Givol D: Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res 54(13): 3391–3395, 1994PubMedGoogle Scholar
  23. 23.
    Ellis PA, Lonning PE, Borresen-Dale A, Aas T, Geisler S, Akslen LA, Salter I, Smith IE, Dowsett M: Absence of p21 expression is associated with abnormal p53 in human breast carcinomas. Br J Cancer 76(4): 480–485, 1997PubMedGoogle Scholar
  24. 24.
    Waldman T, Lengauer C, Kinzler KW, Vogelstein B: Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381: 713–716, 1996PubMedGoogle Scholar
  25. 25.
    Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T: p53 status and the efficacy of cancer therapy in vivo. Science 266: 807–813, 1994PubMedGoogle Scholar
  26. 26.
    Harris CC: Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J Natl Cancer Inst 88(20): 1442–1455, 1996PubMedGoogle Scholar
  27. 27.
    Diab SG, Yu YY, Hilsenbeck SG, Allred DC, and Elledge RM: WAF1/CIP1 protein expression in human breast tumors. Breast Cancer Res Treat 43: 99–103, 1997PubMedGoogle Scholar
  28. 28.
    Beahrs OH, Myers MH (eds), Manual for Staging of Cancer, 2nd edn, pp. 127–133 Philadelphia: Lippincott, 1983Google Scholar
  29. 29.
    Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathol 19(5): 403–410, 1991Google Scholar
  30. 30.
    Thor AD, Liu S, Moore HD II, Edgerton SM: Comparison of mitotic index, in vitro bromodeoxyuridine labeling, and MIB-1 assays to quantitate proliferation in breast cancer. J Clin Oncol 17: 470–477, 1999PubMedGoogle Scholar
  31. 31.
    Benz C, Thor A, Edgerton S, He M, Liu E: HER2/neu overexpression and gene amplification in comedo-type in situ breast cancers. Proc ASCO 10: 46, 1991Google Scholar
  32. 32.
    Liu E, Thor A, He M, Barcos M, Ljung B-M, Benz C: The HER-2 (c-erbB-2) oncogene is frequently amplified in in situ carcinomas of the breast. Oncogene 7: 1027–1032, 1992PubMedGoogle Scholar
  33. 33.
    Cox DR: Regression models and life-tables. J R Statist Soc Ser B 34: 187–220, 1972Google Scholar
  34. 34.
    Clark GM: Prognostic and predictive factors. In: Harris JR, Heilman S, Lippman M, Morrow M, (eds) Diseases of the Breast. Philadelphia, Lippincott-Raven, 1996, 461–485Google Scholar
  35. 35.
    Grambsch P, Therneau TM: Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81: 515–526, 1994Google Scholar
  36. 36.
    Sheer CJ: Cancer cell cycles. Science 274: 1672–1677, 1996PubMedGoogle Scholar
  37. 37.
    EI-Deiry WS, Tokino T, Waldman T, Oliner JD, Velculescu VE, Burrell M, Hill DE, Healy E, Rees JL, Hamilton SR, Kinzler KW, Vogelstein B: Topological control of p21WAF1=CIP1 expression in normal and neoplastic tissues. Cancer Res 55(13): 2910–2919, 1995PubMedGoogle Scholar
  38. 38.
    Waga S, Hannon GJ, Beach D, Stillman B: The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 369: 574–578, 1994PubMedGoogle Scholar
  39. 39.
    Lane DP: Cancer. p53, guardian of the genome. Nature 358: 15–16, 1992PubMedGoogle Scholar
  40. 40.
    Callahan R: p53 mutations, another breast cancer prognostic factor. J Natl Cancer Inst 84: 826–827, 1992PubMedGoogle Scholar
  41. 41.
    Porter PL, Gown AM, Kramp SG, Coltrera MD: Widespread p53 overexpression in human malignant tumors. An immunohistochemical study using methacarn-fixed, embedded tissue. Am J Pathol 140(1): 145–153, 1992PubMedGoogle Scholar
  42. 42.
    Yang ZY, Perkins ND, Ohno T, Nabel EG, Nabel GJ: The p21 cyclin-dependent kinase inhibitor suppresses tumorigenicity in vivo. Nat Med 1(10): 1052–1056, 1995PubMedGoogle Scholar
  43. 43.
    Jacks T, Weinberg RA: Cell-cycle control and its watchman. Nature 381: 643–644, 1996PubMedGoogle Scholar
  44. 44.
    Isola J, Visakorpi T, Holli K, Kallioniemi OP: 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(14): 1109–1114, 1992PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Ann D. Thor
  • Shuquing Liu
  • Dan H. Moore II
  • Qiuju Shi
  • Susan M. Edgerton

There are no affiliations available

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