Cell Growth & Differentiation, Vol 6, Issue 11 1395-1403, Copyright © 1995 by American Association of Cancer Research

ARTICLES

Normal p53 status and function despite the development of drug resistance in human breast cancer cells

K Wosikowski, JT Regis, RW Robey, M Alvarez, JT Buters, JM Gudas and SE Bates
Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.

Loss of or mutations in p53 protein have been shown to decrease both radio- and chemosensitivity. The present study assessed the p53 gene status, ability to arrest in G1 of the cell cycle, the functionality of the p53 transduction pathway, and apoptosis following treatment with radiation in a series of drug-resistant human breast cancer cells to determine whether p53 alterations occur during the development of drug resistance. We used 13 sublines derived from MCF-7, ZR75B, and T47D cells, which were resistant to doxorubicin, paclitaxel, vinblastine, cisplatin, etoposide, and amsacrine. Eleven of 12 drug-resistant sublines retained the parental p53 gene status, as determined by sequence analysis and functional yeast assay; only one subline was found to have acquired a mutation in the p53 gene. The MCF-7 TH subline was found to both acquire mutated p53 and to have major changes in p53 protein expression and function. In 12 other drug-resistant sublines, the G1 checkpoint was conserved or only slightly impaired. A normal accumulation of p53, p21Cip1/Waf1, and Mdm2 proteins and hypophosphorylation of Rb protein occurred in response to radiation with only small differences noted in the kinetics of p53 and p21Cip1/Waf1 induction. Increased susceptibility to apoptosis was found in the ZR75B drug-resistant sublines, whereas no evidence for apoptosis was observed in the ZR75B, MCF-7, and T47D parentals and the MCF-7 and T47D drug-resistant sublines. This effect could not be explained by alterations in bcl-2 or bax expression. Our results demonstrate that alterations in: (a) p53 gene status; (b) ability to arrest in G1; (c) induction of p53 protein and p53-dependent genes; and (d) decreased activation of apoptosis is not a requirement for the onset of drug resistance. The function of p53 appears to be dissociated from drug resistance in our model system.

This article has been cited by other articles:

				J. G. Jackson and O. M. Pereira-Smith Primary and Compensatory Roles for RB Family Members at Cell Cycle Gene Promoters That Are Deacetylated and Downregulated in Doxorubicin-Induced Senescence of Breast Cancer Cells. Mol. Cell. Biol., April 1, 2006; 26(7): 2501 - 2510. [Abstract] [Full Text] [PDF]

				L. Mickley Huff, Z. Wang, A. Iglesias, T. Fojo, and J.-S. Lee Aberrant Transcription from an Unrelated Promoter Can Result in MDR-1 Expression following Drug Selection In vitro and in Relapsed Lymphoma Samples Cancer Res., December 15, 2005; 65(24): 11694 - 11703. [Abstract] [Full Text] [PDF]

				Y. Ohiro, A. Usheva, S. Kobayashi, S. L. Duffy, R. Nantz, D. Gius, and N. Horikoshi Inhibition of Stress-Inducible Kinase Pathways by Tumorigenic Mutant p53 Mol. Cell. Biol., January 1, 2003; 23(1): 322 - 334. [Abstract] [Full Text]

				G. M. Wulf, Y.-C. Liou, A. Ryo, S. W. Lee, and K. P. Lu Role of Pin1 in the Regulation of p53 Stability and p21 Transactivation, and Cell Cycle Checkpoints in Response to DNA Damage J. Biol. Chem., December 6, 2002; 277(50): 47976 - 47979. [Abstract] [Full Text] [PDF]

				O. Greco, S. Rossiter, C. Kanthou, L. K. Folkes, P. Wardman, G. M. Tozer, and G. U. Dachs Horseradish Peroxidase-mediated Gene Therapy: Choice of Prodrugs in Oxic and Anoxic Tumor Conditions Mol. Cancer Ther., December 1, 2001; 1(2): 151 - 160. [Abstract] [Full Text] [PDF]

				A. W. Tong, M. H. Papayoti, G. Netto, D. T. Armstrong, G. Ordonez, J. M. Lawson, and M. J. Stone Growth-inhibitory Effects of CD40 Ligand (CD154) and Its Endogenous Expression in Human Breast Cancer Clin. Cancer Res., March 1, 2001; 7(3): 691 - 703. [Abstract] [Full Text]

				F. Pirnia, M. Breuleux, E. Schneider, M. Hochmeister, S. E. Bates, A. Marti, M. A. Hotz, D. C. Betticher, and M. M. Borner Uncertain Identity of Doxorubicin-Resistant MCF-7 Cell Lines Expressing Mutated p53 J Natl Cancer Inst, September 20, 2000; 92(18): 1535 - 1536. [Full Text] [PDF]

				N. J. Donato, M. Perez, H. Kang, Z. H. Siddik, Y.-H. Ling, and R. Perez-Soler EGF Receptor and p21WAF1 Expression are Reciprocally Altered as ME-180 Cervical Carcinoma Cells Progress from High to Low Cisplatin Sensitivity Clin. Cancer Res., January 1, 2000; 6(1): 193 - 202. [Abstract] [Full Text]

				Z.-H. Qin, R.-W. Chen, Y. Wang, M. Nakai, D.-M. Chuang, and T. N. Chase Nuclear Factor kappa B Nuclear Translocation Upregulates c-Myc and p53 Expression during NMDA Receptor-Mediated Apoptosis in Rat Striatum J. Neurosci., May 15, 1999; 19(10): 4023 - 4033. [Abstract] [Full Text] [PDF]

				C. L. Reimer, A. M. Borras, S. K. Kurdistani, J. R. Garreau, M. Chung, S. A. Aaronson, and S. W. Lee Altered Regulation of Cyclin G in Human Breast Cancer and Its Specific Localization at Replication Foci in Response to DNA Damage in p53+/+ Cells J. Biol. Chem., April 16, 1999; 274(16): 11022 - 11029. [Abstract] [Full Text] [PDF]

				M. S. Orr, N. C. Watson, S. Sundaram, J. K. Randolph, P. T. Jain, and D. A. Gewirtz Ionizing Radiation and Teniposide Increase p21waf1/cip1 and Promote Rb Dephosphorylation but Fail to Suppress E2F Activity in MCF-7 Breast Tumor Cells Mol. Pharmacol., September 1, 1997; 52(3): 373 - 379. [Abstract] [Full Text]