Drug-resistant breast cancer cells frequently retain expression of a functional wild-type p53 protein

Jean M. Gudas, Hoang Nguyen, Tao Li, Lisa Sadzewicz, Robert Robey, Katja Wosikowksi, Kenneth H Cowan

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Abnormalities in the p53 tumor suppressor gene have been shown to affect cellular processes related to cell cycle control and gene amplification. In this study we compare the status and function of wild-type p53 in MCF-7 breast cancer cells with sublines selected for resistance to chemotherapeutic agents having different mechanisms of action. Sublines that were resistant to melphalan, pyrazafurin, mitoxantrone, etoposide and PALA all retained expression of wild-type p53. Methotrexate-resistant MCF-7 cells were unusual heterozygotes that expressed a wild-type and dominant, in-frame p53 deletion mutant and the doxorubicin-resistant cells expressed only mutant p53. Analysis of the G1 checkpoint after treatment with ionizing radiation revealed that the pyrazafurin-, melphalan- and mitoxantrone-resistant cells arrested strongly in G1. The etoposide- and PALA-resistant cells had an intermediate G1 arrest phenotype and the methotrexate- and doxorubicin-resistant cells had a minimal G1 arrest phenotype, mRNA and protein analyses of downstream effector genes, including p21(CIP1/Waf1), mdm2, Gadd 45 and the retinoblastoma protein, did not entirely differentiate sublines having a strong versus intermediate G1 arrest phenotype. Neither the p53 status nor the strength of the G1 arrest could be correlated with cell survival after ionizing radiation. When drug-sensitive MCF-7 cells were treated with the same chemotherapeutic agents, p53 and p21(CIP1/Waf1) levels increased between 2- and 14-fold. Together these data suggest that other cellular factors likely play a role in overcoming the inhibitory effects of ionizing radiation on p53 in drug-resistant breast cancer cells.

Original languageEnglish (US)
Pages (from-to)1417-1427
Number of pages11
JournalCarcinogenesis
Volume17
Issue number7
DOIs
StatePublished - Jul 1 1996

Fingerprint

NSC 224131
Breast Neoplasms
Ionizing Radiation
Pharmaceutical Preparations
Mitoxantrone
Proteins
Melphalan
MCF-7 Cells
Etoposide
Phenotype
Methotrexate
Doxorubicin
cdc Genes
Retinoblastoma Protein
Gene Amplification
Heterozygote
Cell Cycle Checkpoints
Tumor Suppressor Genes
Cell Survival
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research

Cite this

Drug-resistant breast cancer cells frequently retain expression of a functional wild-type p53 protein. / Gudas, Jean M.; Nguyen, Hoang; Li, Tao; Sadzewicz, Lisa; Robey, Robert; Wosikowksi, Katja; Cowan, Kenneth H.

In: Carcinogenesis, Vol. 17, No. 7, 01.07.1996, p. 1417-1427.

Research output: Contribution to journalArticle

Gudas, Jean M. ; Nguyen, Hoang ; Li, Tao ; Sadzewicz, Lisa ; Robey, Robert ; Wosikowksi, Katja ; Cowan, Kenneth H. / Drug-resistant breast cancer cells frequently retain expression of a functional wild-type p53 protein. In: Carcinogenesis. 1996 ; Vol. 17, No. 7. pp. 1417-1427.
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