Breast Cancer Research and Treatment

, Volume 70, Issue 3, pp 205–212

p16INK4a protein expression is associated with poor survival of the breast cancer patients after CMF chemotherapy

  • Sehwan Han
  • Sei-Hyun Ahn
  • Kyeongmee Park
  • Byung-Noe Bae
  • Ki Hwan Kim
  • Hong-Joo Kim
  • Young-Duck Kim
  • Hong-Yong Kim
Article

Abstract

Immunohistochemical assay for p16 protein expession was performed in 192 breast carcinoma patients treated with adjuvant chemotherapy. p16 expression was observed in 78 cases (40.6%). The frequency of p16 expression significantly decreased in moderately differentiated (histologic grade II) cancers, 20 (19.6%) of 102. In poorly differentiated cancers (histologic grade III), p16 expression was not observed in all 16 cases. p16 expression was significantly associated with histologic grade of the breast carcinomas (p < 0.001). The proliferative index (PI: S + G2/M) of individual tumors was measured by DNA flow cytometry. In 114 tumors with PI less than 20%, p16 expression was observed in 59 tumors (49.1%). In the tumors with PI equal or more than 20%, p16 expression was observed in 22 (28.2%) of 78 cases. p16 expression was significantly decreased in the tumor with higher PI (p = 0.003). For the other clinicopathologic variables, no significant association was found with p16 expression status. Immunohistochemical assay for p53 protein expression was performed on the same breast carcinomas. There was no significant association between p16 and p53 expression in breast carcinomas. During median follow-up period of 52 months (range: 40–72 months), 46 patients (25.8%) had recurrent disease and 32 patients (18.91%) died of recurrent disease. p16 expression was observed in 20 (43.5%) of 46 patients with recurrent disease, while its expression was observed in 58 patients (39.7%) of 146 patients who were free of recurrence during the study period. p16 expression had no significant impact on predicting recurrence of breast carcinoma. Fourteen patients (12.2%) of 114 patients whose tumors did not show p16 expression died of recurrent breast carcinoma, whereas 18 patients (23.1%) of 78 patients with p16 expressing tumor died during the follow-up period. There was a significant difference of patient survival according to p16 expression status (p = 0.039). These results indicate that p16 expression is useful in predicting response to chemotherapy in breast cancer patients. p16 protein seems to have a role in tumor growth and differentiation of the breast carcinoma.

breast carcinoma chemotherapy immunohistochemistry p16INK4a prognosis 

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References

  1. 1.
    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, 1993Google Scholar
  2. 2.
    Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS III, Johnson BE, Skolnick MH: A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436-440, 1994Google Scholar
  3. 3.
    Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA: Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368: 753-756, 1994Google Scholar
  4. 4.
    Quelle DE, Ashmun RA, Hannon GJ, Rehberger PA, Trono D, Richter KH, Walker C, Beach D, Sherr CJ, Serrano M: Cloning and characterization of murine p16INK4a and p15INK4b genes. Oncogene 11: 635-645, 1995Google Scholar
  5. 5.
    Zindy F, Quelle DE, Roussel MF, Sherr CJ: Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15: 203-211, 1997Google Scholar
  6. 6.
    Serrano M: The INK4/ARF locus in murine tumorigenesis. Carcinogenesis 21: 865-869, 2000Google Scholar
  7. 7.
    Quesnel B, Fenaux P, Philippe N, Fournier J, Bonneterre J, Preudhomme C, Peyrat JP: Analysis of p16 gene deletion and point mutation in breast carcinoma. Br J Cancer 72: 351-353, 1995Google Scholar
  8. 8.
    Musgrove EA, Lilischkis R, Cornish AL, Lee CS, Setlur V, Seshadri R, Sutherland RL: Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4b and p21WAF1/ CIP1 in human breast cancer. Int J Cancer 63: 584-591, 1995Google Scholar
  9. 9.
    Berns EM, Klijn JG, Smid M, van Staveren IL, Gruis NA, Foekens JA: Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. Br J Cancer 72: 964-967, 1995Google Scholar
  10. 10.
    Dublin EA, Patel NK, Gillett CE, Smith P, Peters G, Barnes DM: Retinoblastoma and p16 proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters. Int J Cancer 79: 71-75, 1998Google Scholar
  11. 11.
    Geradts J, Wilson PA: High frequency of aberrant p16(INK4) expression in human breast cancer. Am J Pathol 149: 15-20, 1996Google Scholar
  12. 12.
    Emig R, Magener A, Ehemann V, Meyer A, Stilgenbauer F, Volkmann M, Wallwiener D, Sinn HP: Aberrant cytoplasmic expression of the p16 prote in in breast cancer is associated with accelerated tumour proliferation. Br J Cancer 78: 1661-1668, 1998Google Scholar
  13. 13.
    Miller C, Aslo A, Campbell M, Kawamata N, Lampkin B, Koeffler H: Alterations of p15, p16, and p18 in osteosarcoma. Cancer Genet Cytogenet 86: 136-142, 1996Google Scholar
  14. 14.
    Marchini S, Codegoni A, Bonazzi C, Chiari S, Broggini M: Absence of deletions but frequent loss of expression of p16 ink4 in human ovarian tumors. Br J Cancer 76: 146-149, 1997Google Scholar
  15. 15.
    Huschtscha LI, Noble JR, Neumann AA, Moy EL, Barry P, Melki JR, Clark SJ, Reddel RR: Loss of p16INK4 expression by methylation is associated with lifespan extention of human mammary epithelial cells. Cancer Res 58: 3508-3512, 1998Google Scholar
  16. 16.
    Han S, Park K, Kim HY, Lee MS, Kim HJ, Kim YD, Yuh YJ, Kim SR, Suh HS: Clinical implication of altered expression of Mad1 protein in human breast carcinoma. Cancer 88: 1623-1632, 2000Google Scholar
  17. 17.
    Lukas J, Aagaard L, Strauss M, Bartek J: Oncogenic aberrations of p16INK4/CDKN2 and cyclin D1 cooperate to deregulate G1 control. Cancer Res 55: 4818-4828, 1995Google Scholar
  18. 18.
    Hui R, Macmillan D, Kenny FS, Musgrove EA, Blamey RW, Nicholson RI, Robertson JFR, Sutherland RL: INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Cancer Res 6: 2777-2787, 2000Google Scholar
  19. 19.
    Otterson GA, Kratzke RA, Coxon A, Kim YW, Kaye FJ: Absence of p16INK4a prote in is restricted to the subset of lung cancer lines that retains wild type pRb. Oncogene 9: 3375-3378, 1994Google Scholar
  20. 20.
    Li Y, Nichols MA, Shay JW, Xiong Y: Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res 54: 6078-6082, 1994Google Scholar
  21. 21.
    Fang XJ, Jin XM, Xu HJ, Liu L, Peng HQ, Hogg D, Roth JA, Yu YH, Xu FJ, Bast RC, Mills GB: Expression of p16 induces transcriptional downregulation of the RB gene. Oncogene 16: 1-8, 1998Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Sehwan Han
    • 1
  • Sei-Hyun Ahn
    • 2
  • Kyeongmee Park
    • 3
  • Byung-Noe Bae
    • 1
  • Ki Hwan Kim
    • 1
  • Hong-Joo Kim
    • 1
  • Young-Duck Kim
    • 1
  • Hong-Yong Kim
    • 1
  1. 1.Departments of SurgeryInje University Sanggye Paik HospitalSeoulKorea
  2. 2.Department of SurgeryAsan Medical CenterSeoulKorea
  3. 3.Departments of PathologyInje University Sanggye Paik HospitalSeoulKorea

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