Summary
Human breast carcinoma is biologically heterogeneous, and its clinical course may vary from an indolent slowly progressive one to a course associated with rapid progression and metastatic spread. It is important to establish prognostic factors which will define subgroups of patients with low vs high risk of recurrence so as to better define the need for additional therapy. Additional characterization of the molecular make-up of breast cancer phenotypes should provide important insights into the biology of breast cancer. In the present study, we investigated apoptosis, expression of p27Kip1 and p53 retrospectively in 181 human breast cancer specimens. In addition, their relevance to the biological behaviour of breast cancer was examined. Our studies found a significant association among high histological grade, high p53, low apoptosis and low p27. Our results also demonstrated that, in human breast cancer, low levels of p27 and apoptotic index (AI) strongly correlated with the presence of lymph node metastasis and decreased patient survival. In node-negative patients, however, p27 also had prognostic value for relapse-free and overall survival in multivariate analysis. Furthermore p27 and AI had predictive value for the benefits of chemotherapy. These latter observations should prompt prospective randomized studies designed to investigate the predictive role of p27 and AI in determining who should receive chemotherapy in node-negative patients.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Allan, D. J., Howell, A., Roberts, S. A., Williams, G. T., Watson, R. J., Coyne, J. D., Clarke, R. B., Laidlaw, I. J. & Potten, C. S. (1992). Reduction in apoptosis relative to mitosis in histologically normal epithelium accompanies fibrocystic change and carcinoma of the premenopausal human breast. J Pathol 167: 25–32.
Alessandrini, A., Chiaur, D. S. & Pagano, M. (1997). Regulation of the cyclin-dependent kinase inhibitor p27 by degradation and phosphorylation. Leukemia 11: 342–345.
Catzavelos, C., Bhattacharya, N., Ung, Y. C., Wilson, J. A., Roncari, L., Sandhu, C., Shaw, P., Yeger, H., Morava-Protzner, I. & Kapusta, L. (1997). Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nature Medicine 3: 227–230.
Doglioni, C., Pelosio, P., Laurino, L., Macri, E., Meggiolaro, E., Favretti, F. & Barbraeschi, M. (1996). p21/WAF1/CIP1 expression in normal mucosa and in adenomas and adenocarcinomas of the colon: its relationship with differentiation. J Pathol 179: 248–253.
El-Deiry, W. S., Tokino, T., Veiculescu, V. E., Levy, D. B., Parsons, R., Trent, L. M., Lin, D., Mercer, W. E., Kinzler, K. W. & Vogelstein, B. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825.
El-Deiry, W. S., Tokino, T. & Waldman, T. (1995). Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. Cancer Res 55: 2910–2919.
Esposito, V., Baldi, A., De Luca, A., Groger, A. M., Loda, M., Giordano, G. G., Caputi, M., Baldi, F., Pagano, M. & Giordano, A. (1997). Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res 57: 3381–3385.
Geske, F. J., Bemis, L. T., Schedin, P. J. & Strange, R. (1994). Function evaluation of genes associated with apoptotic cell death of mammary epithelium. Proc Annu Meet Am Assoc Cancer Res 35: 19–25.
Gray-Bablin, J., Rao, S. & Keyomarsi, K. (1997). Lovastatin induction of cyclin-dependent kinase inhibitors in human breast cells occurs in a cell cycle-independent fashion. Cancer Res 57: 604–609.
Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K. & Elledge, S. T. (1993). The p21 CDK-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805–816.
Hartwell, L. & Kastan, M. B. (1994). Cell cycle control and cancer. Science 266: 1820–1828.
Hoehner, J. C., Hedborg, F., Wiklund, H. J., Olsen, L. & Pahlman, S. (1995). Cellular death in neuroblastoma: in situ correlation of apoptosis and bcl-2 expression. Int J Cancer 62: 19–24.
Hunt, T. & Nasmyth, K. (1993). Dams and sluices. Nature, (Lond) 366: 634–635.
Jiang, M., Shao, Z. M., Wu, J., Lu, J. S., Yu, L. M., Yuan, J. D., Han, Q. X., Shen, Z. Z. & Fontana, J. A. (1997). p21/waf1/cip1 and mdm-2 expression in breast carcinoma patients as related to prognosis. Int J Cancer 74: 529–534.
Katayose, Y., Kim, M., Rakkar, A. N., Li, Z., Cowan, K. H. & Seth, P. (1997). Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res 57: 5441–5445.
Kute, T. E., Shao, Z. M., Sugg, N. K., Long, R. T., Russell, G. B. & Case, L. D. (1992). Cathepsin D as a prognostic indicator for node-negative breast cancer patients using both immunoassays and enzymatic assays. Cancer Res 52: 5198–5203.
Langlois, N. E., Lamb, J., Eremin, O. & Heys, S. D. (1997). Apoptosis in colorectal carcinoma occurring in patients aged 45 years and under: relationship to prognosis, mitosis, and immunohistochemical demonstration of p53, c-myc and bcl-2 protein products. J Pathol 182: 392–397.
Levine, A. J. (1997). p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.
Loda, M., Cukor, B., Tam, S. W., Lavin, P., Fiorentino, M., Draetta, G. F., Jessup, J. M. & Pagano, M. (1997). Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nature Med 3: 231–234.
Marchetti, A., Doglioni, C. & Barbareschi, M. (1996). p21 mRNA and protein expression in non-small cell lung cancer: evidence of p53-independent expression and association with tumoral differentiation. Oncogene 12: 1319–1324.
Noda, A., Ning, Y., Venable, S. F., Pereira-Smith, O. M. & Smith, J. R. (1994). Clonation of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211: 90–98.
Polyak, K., Lee, M. H., Erdjument-Bromage, H., Koff, A., Roberts, J. M., Tempst, P. & Massague, J. (1994a). Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78: 59–66.
Polyak, K., Kato, J. Y., Solomon, M. J., Sherr, C. J., Massague, J., Roberts, J. M. & Koff, A. (1994b). p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8: 9–22.
Porter, P. L., Malone, K. E., Heagerty, P. J., Alexander, G. M., Gatti, L. A., Firpo, E. J., Daling, J. R. & Roberts, J. M. (1997). Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nature Med 3: 222–225.
Raff, M. C. (1992). Social controls on cell survival and cell death. Nature 356: 397–400.
Reynisdottir, I., Polyak, K., Iavarone, A. & Massague, J. (1995). Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev 9: 1831–1845.
Robertson, J. (1997). Prognostic and response markers in the management of breast cancer. Cancer Treatment Rev 23: S41–48.
Saez, S., Clark, G. M. & McGuire, W. L. (1988). Prognostic factors in cancer of the breast. Clin Oncol 2: 103–115.
Shao, Z-M, Jiang, M., Wu, J., Han, Q-X, Zhang, T-Q, Shen, Z-Z & Fontana, J. A. (1996). Identification of spontaneous programmed cell death during development of human breast cancer. Oncology Rep 3: 1133–1136.
Tan, P., Cady, B., Wanner, M., Worland, P., Cukor, B., Magi-Galluzzi, C., Lavin, P., Draetta, G., Pagano, M. & Loda, M. (1997). The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. Cancer Res 57: 1259–1263.
Tomei, L. D., Kanter, P. & Wenner, C. E. (1988). Inhibition of radiation-induced apoptosis in vitro by tumor promoters. Biochem Biophys Res Commun 155: 324–331.
Toyoshima, H. & Hunter, T. (1994). p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78: 67–74.
Wage, S., Hannon, G. J., Beach, D. & Stillman, B. (1994). The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature, (Lond) 369: 574–578.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Wu, J., Shen, ZZ., Lu, JS. et al. Prognostic role of p27Kip1 and apoptosis in human breast cancer. Br J Cancer 79, 1572–1578 (1999). https://doi.org/10.1038/sj.bjc.6690250
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690250
Keywords
This article is cited by
-
Many forks in the path: cycling with FoxO
Oncogene (2008)
-
Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival
Oncogene (2008)
-
The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy
Nature Reviews Cancer (2008)
-
Prognostic molecular markers in early breast cancer
Breast Cancer Research (2004)
-
Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer
Breast Cancer Research (2003)